Association between obstructive sleep apnea and non-alcoholic fatty liver disease: a systematic review and meta-analysis.

The relationship between obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) has been an issue of great concern. The primary purpose of this study was to determine the influence of OSA on the levels of liver enzymes including alanine transaminase (ALT) and aspartate transaminase (AST). The secondary purpose was to estimate the effect of OSA on the histological lesions of NAFLD, such as steatosis, lobular inflammation, ballooning degeneration, fibrosis, as well as NAFLD activity score (NAS). A systematic literature review using PubMed, Cochrane Library, Embase, and Ovid technologies from January 2007 to April 2017 was performed, and 9 studies (2272 participants) that met the selection criteria were evaluated. The present study demonstrated that OSA was related to ALT levels, but no significant correlation was found with AST levels. The subgroup analysis showed that the severity of OSA was associated with ALT levels, not with AST levels. The meta-regression analysis showed that age, sex, homeostasis model assessment, diabetes mellitus, body mass index, and waist circumference did not have a significant effect on the levels of ALT and AST. OSA was also found to be significantly correlated with steatosis, lobular inflammation, ballooning degeneration, and fibrosis, but was not correlated with NAS. OSA was independently related to the development and progression of NAFLD in terms of liver enzyme level and histological alterations. Future studies should investigate the possible relevant mechanisms, thereby guiding the exploration of potential therapeutic implications to prevent the progression of disease.

Nucleos(t)ide analogs improve long-term prognosis in patients with chronic hepatitis B-associated liver failure.

AIM: Chronic hepatitis B-associated liver failure (CHB-LF) is associated with high mortality. Antiviral therapy with nucleoside and nucleotide analogs (NUCs) has been reported to improve the short-term prognosis of patients with CHB-LF. However, the long-term effects of the therapy remain unclear. We undertook a cohort study to investigate the long-term effect of NUC-based antiviral therapy in patients with CHB-LF. METHODS: A total of 976 patients with CHB-LF were enrolled between January 2001 and December 2009 at the Liver Disease Center of Ningbo No. 2 Hospital (Ningbo, China). The patients were divided into the NUC treatment group (n = 412) and control group (n = 564). The propensity score matching method was used to match the patients between the two groups to equilibrate the covariates. Survival analysis was carried out using the matched samples. The Cox proportional hazard model was used for the analysis of prognostic factors. RESULTS: After propensity matching, 262 pairs were successfully matched. No statistically significant difference was observed in the baseline characteristics of the matching pairs (P > 0.05). The long-term survival rate and survival duration of the NUC treatment group were higher than that of the control group (P < 0.05). Gender, age, Model for End-stage Liver Disease values, cholinesterase levels, white blood cell counts, hepatic encephalopathy, concomitant infection, and treatment with NUCs were found to be the independent factors associated with long-term prognosis. CONCLUSION: Antiviral therapy with NUCs may reduce the mortality rate and improve the long-term prognosis of patients with CHB-LF.

Non-invasive diagnosis of non-alcoholic fatty liver disease: Current status and future perspective.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease throughout the world. Hepatocellular carcinoma (HCC) and liver cirrhosis can result from nonalcoholic steatohepatitis (NASH), the severe stage of NAFLD progression. By some estimates, NAFLD affects almost one-third of the world's population, which is completely new and serious public health issue. Unfortunately, NAFLD is diagnosed by exclusion, and the gold standard for identifying NAFLD/NASH and reliably measuring liver fibrosis remains liver biopsy, which is an invasive, costly, time-consuming procedure and involves variable inter-observer diagnosis. With the progress of omics and imaging techniques, numerous non-invasive serological assays have been generated and developed. On the basis of these developments, non-invasive biomarkers and imaging techniques have been combined to increase diagnostic accuracy. This review provides information for the diagnosis and assessment of NAFLD/NASH in clinical practice going forward and may assist the clinician in making an early and accurate diagnosis and in proposing a cost-effective patient surveillance. We discuss newly identified and validated non-invasive diagnostic methods from biopsy-confirmed NAFLD patient studies and their implementation in clinical practice, encompassing NAFLD/NASH diagnosis and differentiation, fibrosis assessment, and disease progression monitoring. A series of tests, including 20-carboxy arachidonic acid (20-COOH AA) and 13,14-dihydro-15-keto prostaglandin D2 (dhk PGD2), were found to be potentially the most accurate non-invasive tests for diagnosing NAFLD. Additionally, the Three-dimensional magnetic resonance imaging (3D-MRE), combination of the FM-fibro index and Liver stiffness measurement (FM-fibro LSM index) and the machine learning algorithm (MLA) tests are more accurate than other tests in assessing liver fibrosis. However, it is essential to use bigger cohort studies to corroborate a number of non-invasive diagnostic tests with extremely elevated diagnostic values.

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.

[Clinical analysis of hepatitis B virus mutations related to adefovir dipivoxil among patients with chronic hepatitis B virus infection in eastern Zhejiang province].

OBJECTIVE: To explore the clinical characteristics of hepatic B virus (HBV) mutations related to adefovir dipivoxil (ADV) among patients with chronic HBV infection in eastern Zhejiang province and provide some reference values on normative usage of antiviral drugs. METHODS: The data of chronic HBV-infected patients with HBV mutations related to ADV (n = 88) and non-mutation (n = 202) from June 2008 to August 2010 were analyzed retrospectively. The gene resistance mutations of HBV P region were analyzed by gene sequencing. And the HBV genotypes, HBV serum markers, HBV DNA levels and liver imaging findings were also analyzed. RESULTS: There were 9 cases with pre-existing mutations in 88 patients. The mutated sites were multiple and complicated. And the mutated sites related to other antiviral drugs were all accompanied by ADV-related mutations. The single mutated site was mostly at rtA181T (46.59%) and at rtV214A (11.36%). There were 27 cases (30.68%) with ≥ two mutated sites. The constituent ratios of males, end-stage liver diseases, complicated nonalcoholic fatty liver disease (NAFLD) and HBV genotype C infection in the mutation group were higher than those in the non-mutation group (P < 0.01, < 0.01, 0.019, 0.045). The average ages in the mutation group were also higher than those in the non-mutation group (P < 0.001). But the constituent ratios of HBeAg positivity and the levels of HBV DNA were lower (P = 0.002, 0.02). CONCLUSION: There may be some cases with pre-existing ADV-related mutations in ADV treatment-naive patients. The mutated sites occur at multiple loci, mostly at rtA181T and rtV214A. The male patients and those with a longer history of HBV infection, HBeAg negativity, HBV genotype C infection, illness progression and complicated NAFLD may be more susceptible to mutation. It is important for patients to accept and implement standardized regimens of antiviral drugs so as to prevent resistance and avoid salvage therapy.

[Clinical analysis and literature review of six cases of neurogenic pulmonary edema].

OBJECTIVE: To explore the early diagnosis and correct treatment of neurogenic pulmonary edema (NPE) and review the literature. METHODS: Retrospective analysis was performed in six patients diagnosed as NPE who were admitted to the emergency department of Tianjin Third Central Hospital from March 2017 to March 2021. RESULTS: Six patients had acute onset, presenting severe dyspnea and hypoxemia, and obvious wet rales could be heard in both lungs. The white blood cell count (WBC) increased to varying degrees (11-22)×109/L, procalcitonin (PCT) was normal, or slightly increased, sputum bacteriological examination was negative, and oxygenation index was < 200 mmHg (1 mmHg ≈ 0.133 kPa). Chest CT mainly showed patchy or patchy exudation. The lesions were of different sizes and were not distributed according to lobes. By reducing intracranial pressure, ventilator assisted breathing, liquid therapy, anti-infection therapy with antibiotics, nutritional support, all six patients were well and discharged, and no one died of NPE. CONCLUSIONS: NPE has complex condition, acute onset and rapid development. Early diagnosis and correct treatment can improve the success rate of treatment and prognosis of patients with NPE.

[Analysis on clinical characteristics of patients undergoing CPR in department of emergency and factors influencing the success of resuscitation].

OBJECTIVE: To analyze the clinical data and characteristics of patients undergoing cardiopulmonary resuscitation (CPR) in the emergency department and the factors affecting the success of resuscitation, so as to allocate medical resources in emergency department, improve the CPR process and increase the success rate of CPR. METHODS: 538 patients with cardiac arrest who were registered by Utstein in the emergency department of the Third Central Hospital of Tianjin from December 2009 to December 2019 were selected as study subjects. The clinical data and characteristics were analyzed. According to whether the resuscitation was successful, the patients were divided into successful group and failed group, and the factors influencing success of resuscitation were analyzed. RESULTS: A total of 538 patients were enrolled in this study, with an average age of (65.53±15.56) years old. The number of patients aged 71-80 years old was the largest (145 cases, 27.0%), followed by those aged 61-70 years old (105 cases, 19.5%) and 51-60 years old (99 cases, 18.4%). The main causes of cardiac arrest were acute myocardial infarction in 203 cases (37.7%), unknown causes in 77 cases (14.3%) and other cardiac causes in 61 cases (11.3%). The initial types of heart rhythm were no pulse electrical activity (215 cases, 40.0%) and cardiac arrest (179 cases, 33.3%). In this study, 195 patients were resuscitated successfully, and the success rate of recovery was 36.2%. Compared with the successful group, the time of onset to resuscitation (minutes: 14.94±1.03 vs. 9.02±1.05), start time of epinephrine application (minutes: 8.50±0.02 vs. 4.21±0.16), time of onset to endotracheal intubation success (minutes: 9.56±1.87 vs. 5.86±0.84) and total duration of CPR (minutes: 48.75±1.73 vs. 35.39±2.51) in the failed group were significantly prolonged (all P < 0.05), and the cumulative epinephrine dosage was significantly increased (mg: 8.48±4.81 vs. 6.31±4.86, P < 0.05). There were significant differences in the location of onset and main causes of cardiac arrest between the two groups (both P < 0.05), but there were no significant differences in gender, age, initial heart rate type and the proportion of defibrillation (all P > 0.05). Binary Logistic analysis showed that the time from onset to resuscitation [odds ratio (OR) = 1.763, 95% confidence interval (95%CI) was 1.713-1.804, P = 0.000], cumulative dosage of epinephrine (OR = 1.759, 95%CI was 1.708-1.765, P = 0.000), time of onset to endotracheal intubation success (OR = 1.023, 95%CI was 0.988-1.047, P = 0.008) and start time of epinephrine use (OR = 1.819, 95%CI was 1.785-1.946, P = 0.002) were risk factors for successful resuscitation (all P < 0.05). CONCLUSIONS: Cardiogenic disease is the main cause of cardiac arrest, and the time from onset to resuscitation, cumulative dosage of epinephrine, success time of endotracheal intubation and time of epinephrine application are independent factors influencing the success of resuscitation in department of emergency.

[Preparation of paraoxonase liposomes and their pharmacokinetics in rats].

OBJECTIVE: To prepare paraoxonase 1 (PON1) liposomes, and investigate pharmacokinetics of common PON1 liposomes (L-PON1) and polyethylene glycol-modified PON1 long circulating liposomes (PEG-PON1-LCL) in rats after intravenous administration. METHODS: L-PON1 and PEG-PON1-LCL were prepared by film dispersion method. The entrapment efficiency, mean diameter and Zeta potential of the liposomes were measured, and the stability was evaluated. Thirty-six Wistar rats were divided into three groups according to random number table, with 12 rats in each group. The rats were intravenously administrated with PON1, L-PON1 or PEG-PON1-LCL 700 U/kg, respectively. The activity of PON1 in serum was determined by phenyl acetate method, the activity of PON1 at different time points after drug administration was compared with that before drug administration, and the difference value was considered as the activity of exogenous PON1, and PON1 activity-time curve was plotted. The pharmacokinetic parameters were calculated and analyzed by DAS 2.0 pharmacokinetic program and SPSS 17.0. RESULTS: The entrapment efficiencies of L-PON1 and PEG-PON1-LCL were above 85%, the mean diameter was about 126 nm, and Zeta potential was -14.35 mV. After 2 weeks of preservation, the above parameters showed no obvious change, indicating that liposomes had good stability and the properties of preparations were basically stable. Compared with purified PON1 administration, after L-PON1 and PEG-PON1-LCL administration, the activity of PON1 was increased, the half-life of PON1 activity in rats was significantly prolonged [the half-life of distribution (T1/2α, hours): 0.142±0.018, 0.147±0.021 vs. 0.126±0.022; the half-life of clearance (T1/2ß, hours): 3.877±1.010, 4.520±1.117 vs. 1.226±0.422], the area under PON1 activity-time curve (AUC) was significantly increased [AUC from 0 hour to 24 hours (AUC0-24, U×h-1×L-1): 499.305±64.710, 563.576±70.450 vs. 18.053±2.190; AUC from the immediate injection to the disappearance of PON1 activity (AUC0-∞, U×h-1×L-1): 516.256±60.940, 587.801±76.210 vs. 21.044±3.250], the apparent volume of distribution (Vd) and clearance (CL) were significantly decreased [Vd (L): 0.140±0.065, 0.144±0.064 vs. 0.493±0.032, CL (L/h): 0.039±0.008, 0.034±0.006 vs. 0.952±0.082, all P < 0.05]. There was no significant difference in pharmacokinetics between L-PON1 and PEG-PON1-LCL. CONCLUSIONS: The film dispersion method prepared PON1 liposomes have high entrapment efficiency and small particle size with a good stability. Both liposomes can raise PON1 activity in vivo, change the pharmacokinetics of PON1 in vivo, prolong the resident time of PON1 in the blood circulating system, and compensate for the short half-life of PON1 in vivo.

Physiological and subjective responses after psychosocial stress in Chinese hepatitis B patients.

Compared with healthy participants, Chinese patients with hepatitis B (HB) experience more psychosocial stress. The present study provided the first examination of physiological and subjective responses to stress in Chinese HB patients. A standard psychosocial stressor, the Trier Social Stress Test (TSST), was administered to 26 Chinese HB patients and 24 healthy control participants. Cortisol concentrations were measured in blood samples collected before and after the stressor. Self-reported emotional responses and cardiovascular measures were examined before and after the TSST. Depression and anxiety were assessed using Hospital Anxiety and Depression Scale. Chinese HB patients exhibited higher cortisol response to the stressor than healthy control participants. Compared with healthy participants, Chinese HB patients showed higher levels of anxiety, depression and nervousness, and lower levels of calmness after the TSST. HB patients reported more negative life events in the previous 6 months and obtained higher adversity scores, as compared with control participants. Significant correlations were obtained between adversity scores and change cortisol secretion after TSST in HB patients, but not in healthy participants. This study firstly demonstrates that physiological and subjective responses to psychosocial stress among Chinese HB patients were different from that in healthy control participants.

Resistant mutants induced by adefovir dipivoxil in hepatitis B virus isolates.

AIM: To investigate the loci of adefovir dipivoxil (ADV)-induced resistance in hepatitis B virus (HBV) isolates and optimize the management of ADV-treated patients. METHODS: Between June 2008 and August 2010, a cross-sectional control study was conducted comprising 79 patients with chronic HBV infection-related liver disease who had been administered ADV monotherapy. Patients underwent liver imaging. Serum DNA extracts were analyzed for HBV DNA levels, genotypes, and serology markers, and deep sequencing of the HBV P gene was performed. RESULTS: ADV-resistant patients were found either with a single mutated locus, or with coexisting mutated loci. The most prevalent mutations were rtA181T, rtV214A, and rtN236T. Twenty-six patients had more than two mutated loci. The mutants were distributed among the patients without any significant affinity for gender, age, end-stage of liver disease, complications of non-alcoholic fatty liver disease, or HBV DNA levels. Patients with the rtA181T mutant were primarily infected with genotype C and e-antigen negative HBV, while patients with the rtN236T mutant were primarily infected by genotype B HBV (χ(2) = 6.004, 7.159; P = 0.023, 0.007). The duration of treatment with ADV was shorter in the single mutant group compared with the multi-mutant group (t = 2.426, P = 0.018). CONCLUSION: Drug-resistant HBV mutants are complex and diverse. Patients should receive the standard and first-line antiviral treatment, strictly comply with medication dosage, and avoid short-term withdrawal.