Questionnaire survey on knowledge, attitudes, and behaviour towards viral hepatitis among the Hong Kong public.

INTRODUCTION: We aimed to identify gaps in knowledge, attitudes, and behaviours towards viral hepatitis among the Hong Kong public and provide insights to optimise local efforts towards achieving the World Health Organization's viral hepatitis elimination target. METHODS: A descriptive, cross-sectional, self-reported web-based questionnaire was administered to 500 individuals (aged ≥18 years) in Hong Kong. Questionnaire items explored the awareness and perceptions of viral hepatitis-related liver disease(s) and associated risk factors in English or traditional Chinese. RESULTS: The majority (>80%) were aware that chronic hepatitis B and/or C could increase the risks of developing liver cirrhosis, cancer, and/or failure. Only 55.8% had attended health screenings in the past 2 years, and 67.6% were unaware of their family's history of liver diseases. Misperceptions surrounding the knowledge and transmission risks of viral hepatitis strongly hint at the presence of social stigmatisation within the community. Many misperceived viral hepatitis as airborne or hereditary, and social behaviours (casual contact or dining with an infected person) as a transmission route. Furthermore, 62.4% were aware of hepatitis B vaccination, whereas 19.0% knew that hepatitis C cannot be prevented by vaccination. About 70% of respondents who were aware of mother-to-child transmission were willing to seek medical consultation in the event of pregnancy. Gaps in knowledge as well as the likelihood of seeking screening were observed across all age-groups and education levels. CONCLUSIONS: Comprehensive hepatitis education strategies should be developed to address gaps in knowledge among the Hong Kong public towards viral hepatitis, especially misperceptions relevant to social stigmatisation and the importance of preventive measures, including vaccination and screening, when exposed to risk factors.

Combination therapy of interferon and nucleotide/nucleoside analogues for chronic hepatitis B.

Chronic hepatitis B is one of the leading causes of cirrhosis and hepatocellular carcinoma globally. At present, seven drugs, including two interferons and five oral nucleos(t)ide analogues (NAs), have been approved for the treatment of chronic hepatitis B. Interferon works by immunomodulation, but is successful in less than a third of treated patients and is a relatively weak antiviral. NAs directly suppress the hepatitis B virus but have limited durability. Based on current data, combination of NA and interferon results in greater viral suppression but does not translate to off-treatment sustained response. Concomitant or sequential treatment also does not make a difference. Combining telbivudine and interferon also runs the risk of severe peripheral neuropathy. On the other hand, interferon switch or additional therapy in patients well controlled with NAs appears to improve the durability of off-treatment response. This article reviews current data on interferon and NA combination and discusses potential future developments.

A randomised comparison of two intranasal dexmedetomidine doses for premedication in children.

We compared sedation levels in children following administration of intranasal dexmedetomidine. One hundred and sixteen children aged between 1 and 8 years were enrolled in this prospective, randomised trial. Children were assigned to receive either intranasal dexmedetomidine 1 µg.kg(-1) (Group 1) or 2 µg.kg(-1) (Group 2). Thirty-one (53%) patients from Group 1 and 38 (66%) patients from Group 2 were satisfactorily sedated at the time of anaesthetic induction. Logistic regression showed a significant interaction effect (p=0.049), with the odds ratio between Group 2 over Group 1 estimated as 1.1 (95% CI 0.5-2.7) for the 1-4 year age group, and 10.5 (95% CI 1.4-80.2) for the 5-8 year age group. Both doses produced a similar level of satisfactory sedation in children aged 1-4 years, whereas 2 µg.kg(-1) resulted in a higher proportion of satisfactory sedation in children aged 5-8 years. There were no adverse haemodynamic effects. We conclude that intranasal dexmedetomidine in a premedication dose of 2 µg.kg(-1) resulted in excellent sedation in children.

Optimal timing for the administration of intranasal dexmedetomidine for premedication in children.

Previous studies have shown that 1 µg.kg(-1) intranasal dexmedetomidine produces significant sedation in children aged between 2 and 12 years. This investigation was designed to evaluate the onset time. One hundred children aged 1-12 years of ASA physical status 1-2 undergoing elective surgery were randomly allocated to five groups. Patients in groups A to D received intranasal dexmedetomidine 1 µg.kg(-1) . Patients in Group E received intranasal placebo (0.9% saline). Children from groups A, B, C, D and E had intravenous cannulation attempted at 30, 45, 60, 75 and 45 min respectively after intranasal drug or placebo administration. Vital signs, behaviour and sedation status of the children were assessed regularly until induction of anaesthesia. More children from groups A to D achieved satisfactory sedation at the time of cannulation when compared to group E (p < 0.001). The proportion of children who achieved satisfactory sedation was not significantly different among groups A to D. Overall 62% of the children who received intranasal dexmedetomidine had satisfactory sedation at the time of cannulation. The median (95% CI) time for onset of sedation was 25 (25-30) min. The median (95% CI) duration of sedation was 85 (55-100) min.

Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B.

BACKGROUND: Metabolic syndrome is associated with non-alcoholic steatohepatitis and cryptogenic cirrhosis. Whether metabolic syndrome affects the severity of chronic hepatitis B (CHB) is unclear. AIM: We aimed to study the relationship between metabolic syndrome and the risk of liver cirrhosis in patients with CHB. METHODS: We prospectively recruited patients with CHB from primary care and hospital clinics for liver stiffness measurement (LSM) with transient elastography to diagnose early cirrhosis. Probable cirrhosis was defined as LSM >or=13.4 kPa. We analysed a subgroup of patients with paired LSM and liver biopsies to validate the accuracy of LSM. RESULTS: 1466 patients had reliable LSM and 134 (9%) patients had adequate liver biopsy. 188 (13%) patients had metabolic syndrome. Histological liver cirrhosis was present in 32/134 (24%) patients. Histological liver cirrhosis was more common among patients who had metabolic syndrome (38%) versus those who did not (11%, p<0.001). The specificity of probable cirrhosis on LSM for histological cirrhosis was 94%. Probable cirrhosis was present in 187 (13%) patients. Metabolic syndrome was more prevalent in patients with probable cirrhosis (24%) than those without cirrhosis (11%, p<0.001). After adjustment for anthropometric, biochemical and virological factors, metabolic syndrome remained an independent factor associated with probable cirrhosis (odds ratio 1.7, 95% confidence interval (CI) 1.1 to 2.6). The odds ratios of probable cirrhosis were 1.4 (95% CI, 0.9 to 2.3), 2.6 (95% CI, 1.7 to 4.3), 4.1 (95% CI, 2.4 to 7.1), 4.0 (95% CI, 1.9 to 8.4) and 5.5 (95% CI, 1.8 to 16.7) in patients with one, two, three, four and five components of metabolic syndrome, respectively. CONCLUSION: Metabolic syndrome is an independent risk factor of liver cirrhosis in CHB.

Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B.

The aim of this study is to know the liver stiffness measurement (LSM) cutoffs for different stages of liver fibrosis in chronic hepatitis B (CHB) and to investigate the effect of alanine aminotransferase (ALT) on LSM. We prospectively studied consecutive CHB patients undergoing liver biopsy and transient elastography examinations. Diagnostic performance of LSM for different degrees of liver fibrosis was evaluated. One hundred and sixty-one CHB patients with adequate liver biopsy sample size were studied. Area under receiver operating characteristics curves of LSM for no fibrosis (F0 vs F1-4), bridging fibrosis (F0-2 vs F3-4) and liver cirrhosis (F0-3 vs F4) was 0.80 (95% CI: 0.68-0.92), 0.87 (95% CI: 0.82-0.93) and 0.93 (95% CI: 0.89-0.97) respectively. For liver cirrhosis, these optimal cutoff values were 8.4 kPa (98% sensitivity), 9.0 kPa (maximum sum of sensitivity and specificity), 13.4 kPa (94% specificity) and 13.4 kPa (maximum diagnostic accuracy, 85%) respectively. Patients with the same fibrosis staging but higher ALT levels tend to have higher LSM, and the diagnostic performance for low stage fibrosis was most seriously affected when ALT was elevated. Different LSM cutoff values and algorithms were derived for normal and elevated ALT levels. Based on these algorithms, liver biopsy can be avoided in 62% and 58% of patients with normal and elevated ALT respectively. In conclusion, transient elastography is a reasonable noninvasive tool to substitute liver biopsy among the lowest and highest risk patients for the assessment of liver fibrosis.

1,25-dihydroxycholecalciferol and parathormone: effects on isolated osteoclast-like and osteoblast-like cells.

The actions of 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] and parathormone, both effective bone-resorptive agents in vivo and in vitro, were tested on CT (osteoclast-like) and PT (osteoblast-like) bone cells maintained in culture. Both agents stimulated acid phosphatase activity and hyaluronate synthesis in the CT cells and decreased alkaline phosphatase, citrate decarboxylation, and collagen synthesis in the PT cells. Calcitonin inhibited the changes induced in the CT but not in the PT cells. The activity of 1,25-(OH)2D3 differed from that of parathormone in one key respect: it did not increase cellular cyclic adenosine monophosphate, whereas parathormone did. Prior incubation of the bone cells with 1,25-(OH)2D3 for 6 to 24 hours made the cells refractory to the effect of parathormone on cyclic adenosine monophosphate formation. These data suggest that 1,25-(OH)2D3 and parathormone induce bone resorption by affecting the same cell types (osteoblasts and osteoclasts) although at different cellular sites.

Review article: long-term safety of oral anti-viral treatment for chronic hepatitis B.

BACKGROUND: Safety profile of nucleos(t)ide analogues is an important issue in view of its widespread use for decades in patients with chronic hepatitis B (CHB). AIM: To review and evaluate the latest evidence on the safety profiles of the six approved nucleoside analogues. METHODS: Relevant articles related to nucleoside analogue safety were selected for review following extensive language- and date-unrestricted, electronic searches of the literature. RESULTS: Nephrotoxicity has been well reported in patients receiving older generations of nucleotide analogues, namely adefovir dipivoxil and tenofovir disoproxil fumarate (TDF). Yet risks of renal failure and renal replacement therapy were similar in patients treated with nucleoside analogues versus nucleotide analogues in real-life setting. Bone toxicity is closely related to nucleoside analogue effect on renal proximal tubular and phosphaturia. Real-life data demonstrated increased risk of hip fracture in patients receiving adefovir but not TDF. The newly approved tenofovir alafenamide (TAF) has improved renal and bone safety profiles compared to TDF. Long-term use of nucleoside analogues eg entecavir does not increase the risk of other cancers. Muscular toxicity may be seen in telbivudine-treated patients so regular monitoring is advised. Peripheral neuropathy and lactic acidosis are rare adverse events. Latest international guidelines support the use of TDF, telbivudine and lamivudine during pregnancy; breastfeeding is not contraindicated during TDF therapy. CONCLUSIONS: Long-term safety profile of nucleoside analogues is now better defined with more data from large real-life cohorts and clinical trials with long-term follow-up. The new nucleotide analogue, TAF is now available with favourable renal and bone safety profiles.

Impact of controlled attenuation parameter on detecting fibrosis using liver stiffness measurement.

BACKGROUND: Liver fibrosis is often accompanied by steatosis, particularly in patients with non-alcoholic fatty liver disease (NAFLD), and its non-invasive characterisation is of utmost importance. Vibration-controlled transient elastography is the non-invasive method of choice; however, recent research suggests that steatosis may influence its diagnostic performance. Controlled Attenuation Parameter (CAP) added to transient elastography enables simultaneous assessment of steatosis and fibrosis. AIM: To determine how to use CAP in interpreting liver stiffness measurements. METHODS: This is a secondary analysis of data from an individual patient data meta-analysis on CAP. The main exclusion criteria for the current analysis were unknown aetiology, unreliable elastography measurement and data already used for the same research question. Aetiology-specific liver stiffness measurement cut-offs were determined and used to estimate positive and negative predictive values (PPV/NPV) with logistic regression as functions of CAP. RESULTS: Two thousand and fifty eight patients fulfilled the inclusion criteria (37% women, 18% NAFLD/NASH, 42% HBV, 40% HCV, 51% significant fibrosis ≥ F2). Youden optimised cut-offs were only sufficient for ruling out cirrhosis (NPV of 98%). With sensitivity and specificity-optimised cut-offs, NPV for ruling out significant fibrosis was moderate (70%) and could be improved slightly through consideration of CAP. PPV for significant fibrosis and cirrhosis were 68% and 55% respectively, despite specificity-optimised cut-offs for cirrhosis. CONCLUSIONS: Liver stiffness measurement values below aetiology-specific cut-offs are very useful for ruling out cirrhosis, and to a lesser extent for ruling out significant fibrosis. In the case of the latter, Controlled Attenuation Parameter can improve interpretation slightly. Even if cut-offs are very high, liver stiffness measurements are not very reliable for ruling in fibrosis or cirrhosis.

Early virological suppression is associated with good maintained response to adefovir dipivoxil in lamivudine resistant chronic hepatitis B.

AIM: To determine the factors affecting the virological response to adefovir dipivoxil (ADV) among patients with lamivudine resistant chronic hepatitis B. METHODS: Chronic hepatitis B virus (HBV) infected patients, who had virological relapse to lamivudine, were switched to ADV monotherapy. RESULTS: Twenty-six patients were treated by ADV for 23 (12-41) months. At baseline, the median log HBV DNA was 7.70 (4.88-9.01) copies/mL. Six (23%) and 8 (31%) of patients had HBV DNA suppressed to below 1000 copies/mL at month 12 and the last follow-up, respectively. On linear regression, patients who had higher HBV DNA at baseline and month 6 have higher HBV DNA at month 12. On Cox proportional hazard model, the hazard ratio for each log step increase in HBV DNA at baseline and month 6 for HBV DNA <1000 copies/mL at the last visit was 0.39 (P = 0.010) and 0.47 (P = 0.027), respectively. Alanine aminotransferase, HBV genotype, rtL80 M mutation and log HBsAg did not affect the HBV DNA response. CONCLUSIONS: The response of lamivudine-resistant patients to ADV is suboptimal. Treatment with ADV when HBV DNA is low, and rapid viral suppression at month 6 increases the chance of maintained viral suppression.

Long-term use of oral nucleos(t)ide analogues for chronic hepatitis B does not increase cancer risk - a cohort study of 44 494 subjects.

BACKGROUND: Patients with chronic hepatitis B (CHB) need long-term antiviral treatment with nucleos(t)ide analogues (NA). Animal studies suggest that some NA may increase cancer risk, but human data are lacking. AIM: To investigate cancer risks in patients with or without NA treatment. METHODS: We conducted a territory-wide cohort study using the database from Hospital Authority in Hong Kong. The diagnosis of CHB and various malignancies was based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes between 2000 and 2012. Patients exposed to any of the oral NA for CHB were included. The primary outcome was incident cancers. A 3-year landmark analysis, with follow-up up to 7 years, was used to evaluate the relative risk of cancers in treated and untreated patients. RESULTS: A total of 44 494 patients (39 712 untreated and 4782 treated) were included in the analysis. During 194 890 patient-years of follow-up, hepatocellular carcinoma developed in 402 (1.0%) untreated patients and 179 (3.7%) treated patients, while other cancers developed in 528 (1.3%) and 128 (2.7%) patients respectively. After propensity score weighting, treated patients had similar risks of all malignancies [weighted hazard ratio (wHR): 1.01, 95% CI: 0.82-1.25, P = 0.899], lung/pleural cancers (wHR: 0.82, 95% CI: 0.52-1.31, P = 0.409) and urinary/renal malignancies (wHR: 1.04, 95% CI: 0.38-2.81, P = 0.944) when compared with untreated patients. CONCLUSIONS: Oral nucleos(t)ide analogue treatment does not appear to increase cancer risk in patients with chronic hepatitis B. Given the beneficial effect on liver outcomes, our data support the current practice of long-term anti-viral therapy.

Statins reduce the risk of liver decompensation and death in chronic viral hepatitis: a propensity score weighted landmark analysis.

BACKGROUND: Decompensated liver disease due to portal hypertension leads to significant morbidity and mortality. Statins can modulate intrahepatic vascular tone, but the clinical significance remains uncertain. AIM: To determine the effects of statin use on the risk of liver decompensation and death among patients with chronic viral hepatitis. METHODS: We conducted a population wide cohort study using a hospital based database from the Hong Kong Hospital Authority. Adults with chronic viral hepatitis without prior liver decompensation were identified from 2000 to 2012 by International Classification of Diseases, Ninth Revision, Clinical Modification, diagnostic codes. Statin use was defined as a cumulative defined daily dose of >28. Landmark analysis was used to overcome immortal time bias. Propensity score weighting was further performed to minimise baseline confounders. Primary outcome was a composite of portal hypertension related liver decompensation events, with adjustment for death as a competing risk. RESULTS: A total of 69 184 patients with chronic viral hepatitis (2053 statin users and 67 131 statin non-users) were identified for the 2-year landmark analysis. After propensity score weighting of 23 baseline covariates, statin use was associated with a significant reduction in composite liver decompensation events (HR: 0.55; 95% CI: 0.36-0.83; P = .005), ascites (HR: 0.57; 95% CI: 0.36-0.92; P = .02), and a dose-dependent decrease in death (HR: 0.87; 95% CI: 0.76-0.99; P = .035) relative to no statin use. CONCLUSIONS: Patients with chronic viral hepatitis who used statins have a reduced risk of liver decompensation and death compared to non-users in this propensity score weighted landmark analysis.

Laboratory parameter-based machine learning model for excluding non-alcoholic fatty liver disease (NAFLD) in the general population.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) affects 20%-40% of the general population in developed countries and is an increasingly important cause of hepatocellular carcinoma. Electronic medical records facilitate large-scale epidemiological studies, existing NAFLD scores often require clinical and anthropometric parameters that may not be captured in those databases. AIM: To develop and validate a laboratory parameter-based machine learning model to detect NAFLD for the general population. METHODS: We randomly divided 922 subjects from a population screening study into training and validation groups; NAFLD was diagnosed by proton-magnetic resonance spectroscopy. On the basis of machine learning from 23 routine clinical and laboratory parameters after elastic net regulation, we evaluated the logistic regression, ridge regression, AdaBoost and decision tree models. The areas under receiver-operating characteristic curve (AUROC) of models in validation group were compared. RESULTS: Six predictors including alanine aminotransferase, high-density lipoprotein cholesterol, triglyceride, haemoglobin A1c , white blood cell count and the presence of hypertension were selected. The NAFLD ridge score achieved AUROC of 0.87 (95% CI 0.83-0.90) and 0.88 (0.84-0.91) in the training and validation groups respectively. Using dual cut-offs of 0.24 and 0.44, NAFLD ridge score achieved 92% (86%-96%) sensitivity and 90% (86%-93%) specificity with corresponding negative and positive predictive values of 96% (91%-98%) and 69% (59%-78%), and 87% of overall accuracy among 70% of classifiable subjects in the validation group; 30% of subjects remained indeterminate. CONCLUSIONS: NAFLD ridge score is a simple and robust reference comparable to existing NAFLD scores to exclude NAFLD patients in epidemiological studies.

Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver fibrosis in patients with NAFLD.

BACKGROUND: The accuracy of available non-invasive tools for staging severe fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) is still limited. AIM: To assess the diagnostic performance of paired or serial combination of non-invasive tools in NAFLD patients. METHODS: We analysed data from 741 patients with a histological diagnosis of NAFLD. The GGT/PLT, APRI, AST/ALT, BARD, FIB-4, and NAFLD Fibrosis Score (NFS) scores were calculated according to published algorithms. Liver stiffness measurement (LSM) was performed by FibroScan. RESULTS: LSM, NFS and FIB-4 were the best non-invasive tools for staging F3-F4 fibrosis (AUC 0.863, 0.774, and 0.792, respectively), with LSM having the highest sensitivity (90%), and the highest NPV (94%), and NFS and FIB-4 the highest specificity (97% and 93%, respectively), and the highest PPV (73% and 79%, respectively). The paired combination of LSM or NFS with FIB-4 strongly reduced the likelihood of wrongly classified patients (ranging from 2.7% to 2.6%), at the price of a high uncertainty area (ranging from 54.1% to 58.2%), and of a low overall accuracy (ranging from 43% to 39.1%). The serial combination with the second test used in patients in the grey area of the first test and in those with high LSM values (>9.6 KPa) or low NFS or FIB-4 values (<-1.455 and <1.30, respectively) overall increased the diagnostic performance generating an accuracy ranging from 69.8% to 70.1%, an uncertainty area ranging from 18.9% to 20.4% and a rate of wrong classification ranging from 9.2% to 11.3%. CONCLUSION: The serial combination of LSM with FIB-4/NFS has a good diagnostic accuracy for the non-invasive diagnosis of severe fibrosis in NAFLD.

Significant positive association of endotoxemia with histological severity in 237 patients with non-alcoholic fatty liver disease.

BACKGROUND: Patients with nonalcoholic steatohepatitis (NASH) have gut dysbiosis and intestinal bacterial overgrowth. AIM: To test the hypothesis that endotoxemia is associated with the histological severity of nonalcoholic fatty liver disease (NAFLD) and determine factors associated with endotoxemia. METHODS: The endotoxemia markers lipopolysaccharide-binding protein (LBP) and endotoxin levels were measured in 237 NAFLD patients 1 day before liver biopsy. Biomarkers of liver injury and transient elastography were performed as additional markers of disease severity. RESULTS: A total of 114/237 (48%) patients had NASH and 80/237 (34%) had F2-4 fibrosis. LBP was correlated with lobular inflammation (P=.001), while both LBP (P=.0004) and endotoxin levels (P=0.008) were correlated with fibrosis. LBP was also correlated with cytokeratin-18 fragments (P=.002) and aspartate aminotransferase-to-alanine aminotransferase ratio (P=.006), and both LBP (P=.019) and endotoxin (P=.006) were correlated with liver stiffness measurement by transient elastography. LBP was increased in patients with NASH (15.3±4.6 vs 13.8±3.3 µg/mL; P=.005) and F2-4 fibrosis (15.4±4.4 vs 14.0±3.7 µg/mL; P=.008). Interestingly, patients harbouring the TM6SF2 rs58542926 T allele that predispose to NAFLD/NASH had higher LBP level. By multivariate analysis, gender, higher body mass index and glycated haemoglobin, and TM6SF2 variants were independent factors associated with increased LBP level. CONCLUSIONS: Endotoxemia is positively associated with NASH and significant fibrosis. The association between TM6SF2 and endotoxemia warrants further investigations. The findings may shed light on the pathogenesis of NASH and inform a novel treatment target.

Prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease is prevalent in affluent countries and is strongly associated with metabolic syndrome. AIM: To study the prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-alcoholic fatty liver disease. METHODS: 73 consecutive patients with biopsy-proven non-alcoholic fatty liver disease and no history of diabetes underwent comprehensive metabolic screening. Diagnosis of diabetes and impaired glucose regulation was based on the 2006 American Diabetes Association criteria. RESULTS: The prevalence of undiagnosed diabetes and impaired glucose tolerance in non-alcoholic fatty liver disease patients was 33% and 29%, respectively. Among patients with 2-h plasma glucose above 7.8 mm, 47% had normal fasting glucose (below 5.6 mm). Impaired glucose tolerance was more common in patients with non-alcoholic steatohepatitis than those with simple hepatic steatosis (P = 0.036), and 2-h plasma glucose correlated with fibrosis stage (Spearman coefficient: 0.25, P = 0.046). In a binary logistic regression analysis, high fasting glucose and low high-density lipoprotein cholesterol were independent factors associated with diabetes. Nevertheless, if oral glucose tolerance test was only performed in non-alcoholic fatty liver disease patients with impaired fasting glucose, 20.8% of diabetes cases would be missed. CONCLUSIONS: Isolated postchallenge hyperglycaemia is common among Chinese non-alcoholic fatty liver disease patients without history of diabetes. It is associated with histological severe disease, and cannot be accurately predicted by any fasting glucose cut-off.