Liver histopathological lesions is severe in patients with normal alanine transaminase and low to moderate hepatitis B virus DNA replication.

BACKGROUND: Chronic hepatitis B virus (HBV) infection remains a major global public health problem. Chronic hepatitis B (CHB) patients can be divided into treatment indication and non-treatment indication individuals according to alanine transaminase (ALT), HBV DNA, serum hepatitis B e antigen status, disease status [liver cirrhosis, hepatocellular carcinoma (HCC), or liver failure], liver necroinflammation or fibrosis, patients' age, and family history of HCC or cirrhosis. For example, normal ALT patients in 'immune-tolerant' phase with HBV DNA higher than 107 or 2 × 107 IU/mL, and those in 'inactive-carrier' phase with HBV DNA lower than 2 × 103 IU/mL do not require antiviral therapy. However, is it reasonable to set the defined values of HBV DNA as the fundamental basis to estimate the disease state and to determine whether to start treatment? In fact, we should pay more attention to those who do not match the treatment indications (gray-zone patients both in the indeterminate phase and in the 'inactive-carrier' phase). AIM: To analyze the correlation of HBV DNA level and liver histopathological severity, and to explore the significance of HBV DNA for CHB with normal ALT. METHODS: From January 2017 to December 2021, a retrospective cross-sectional set of 1299 patients with chronic HBV infection (HBV DNA > 30 IU/mL) who underwent liver biopsy from four hospitals, including 634 with ALT less than 40 U/L. None of the patients had received anti-HBV treatment. The degrees of liver necroinflammatory activity and liver fibrosis were evaluated according to the Metavir system. On the basis of the HBV DNA level, patients were divided into two groups: Low/moderate replication group, HBV DNA ≤ 107 IU/mL [7.00 Log IU/mL, the European Association for the Study of the Liver (EASL) guidelines] or ≤ 2 × 107 IU/mL [7.30 Log IU/mL, the Chinese Medical Association (CMA) guidelines]; high replication group, HBV DNA > 107 IU/mL or > 2 × 107 IU/mL. Relevant factors (demographic characteristics, laboratory parameters and noninvasive models) for liver histopathological severity were analyzed by univariate analysis, logistics analysis and propensity score-matched analysis. RESULTS: At entry, there were 21.45%, 24.29%, and 30.28% of the patients had liver histopathological severities with ≥ A2, ≥ F2, and ≥ A2 or/and ≥ F2, respectively. HBV DNA level (negative correlation) and noninvasive model liver fibrosis 5 value (positive correlation) were independent risk factors for liver histopathological severities (liver necroinflammation, liver fibrosis, and treatment indication). The AUROCs of the prediction probabilities (PRE_) of the models mentioned above (< A2 vs ≥ A2, < F2 vs ≥ F2, < A2 and < F2 vs ≥ A2 or/and ≥ F2) were 0.814 (95%CI: 0.770-0.859), 0.824 (95%CI: 0.785-0.863), and 0.799 (95%CI: 0.760-0.838), respectively. HBV DNA level (negative correlation) was still an independent risk factor when diagnostic models were excluded, the P values (< A2 vs ≥ A2, < F2 vs ≥ F2, < A2 and < F2 vs ≥ A2 or/and ≥ F2) were 0.011, 0.000, and 0.000, respectively. For the propensity score-matched pairs, whether based on EASL guidelines or CMA guidelines, the group with significant liver histology damage (≥ A2 or/and ≥ F2) showed much lower HBV DNA level than the group with non- significant liver histology damage (< A2 and < F2). Patients in the moderate replication group (with indeterminate phase) had the most serious liver disease pathologically and hematologically, followed by patients in the low replication group (with 'inactive-carrier' phase) and then the high replication group (with 'immune-tolerant' phase). CONCLUSION: HBV DNA level is a negative risk factor for liver disease progression. The phase definition of CHB may be revised by whether the level of HBV DNA exceeds the detection low limit value. Patients who are in the indeterminate phase or 'inactive carriers' should receive antiviral therapy.

Clinicopathologic features and molecular analysis of enterovirus 71 infection: report of an autopsy case from the epidemic of hand, foot and mouth disease in China.

A 15-month boy with fatal hand, foot, and mouth disease (HFMD) exhibited atypical symptoms and progressed rapidly to death. An autopsy was performed the next day and tissue sections were stained for histopathological examination. His intestinal samples were tested for enterovirus 71 (EV71), and the whole-genome sequence of EV71 was analyzed. An autopsy revealed that the central nervous system, lungs, and gut displayed severe meningitis and brainstem encephalitis, remarkable pulmonary congestion, edema, moderate inflammatory infiltration, and hemorrhage as well as intestinal mucosal congestion, epithelial necrosis, thinning intestinal wall, and submucosal lymphoid follicular hyperplasia. The heart showed myocardial interstitial congestion, myocardial edema, and some inflammatory infiltrates. There were no significant alterations in the architecture of other organs. EV71 antigen and apoptotic cells were detected in brain, lung and intestine by immunohistochemical staining and TUNEL (TdT-mediated dUTP nick-end labeling) respectively. Intestinal contents and intestinal autopsy samples of this case were positive for EV71, and the EV71 strain was classified as subgenogroup C4. In China, the severe forms of HFMD were mostly caused by EV71 subgenogroup C4 infection. Severe intestinal damages may relate to EV71 subgenogroup C4 infection. Thus, children with severe EV71 HFMD may have serious pathological changes in their central nervous system, lungs, and gut. Physicians should pay special attention to infants with atypical symptoms, particularly in EV71 epidemic areas for early diagnosis and treatment.