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ObjectiveData on serial liver biochemistries of patients infected by different human coronaviruses (HCoVs) are lacking. The impact of liver injury on adverse clinical outcomes in coronavirus disease 2019 (COVID-19) patients remains unclear.DesignThis was a retrospective cohort study using data from a territory-wide database in Hong Kong. COVID-19, severe acute respiratory syndrome (SARS) and other HCoV patients were identified by diagnosis codes and/or virological results. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation was defined as ALT/AST ≥2 × upper limit of normal (ie, 80 U/L). The primary end point was a composite of intensive care unit (ICU) admission, use of invasive mechanical ventilation and/or death.ResultsWe identified 1040 COVID-19 patients (mean age 38 years, 54% men), 1670 SARS patients (mean age 44 years, 44% men) and 675 other HCoV patients (mean age 20 years, 57% men). ALT/AST elevation occurred in 50.3% SARS patients, 22.5% COVID-19 patients and 36.0% other HCoV patients. For COVID-19 patients, 53 (5.1%) were admitted to ICU, 22 (2.1%) received invasive mechanical ventilation and 4 (0.4%) died. ALT/AST elevation was independently associated with primary end point (adjusted OR (aOR) 7.92, 95% CI 4.14 to 15.14, p<0.001) after adjusted for albumin, diabetes and hypertension. Use of lopinavir–ritonavir ±ribavirin + interferon beta (aOR 1.94, 95% CI 1.20 to 3.13, p=0.006) and corticosteroids (aOR 3.92, 95% CI 2.14 to 7.16, p<0.001) was independently associated with ALT/AST elevation.ConclusionALT/AST elevation was common and independently associated with adverse clinical outcomes in COVID-19 patients. Use of lopinavir–ritonavir, with or without ribavirin, interferon beta and/or corticosteroids was independently associated with ALT/AST elevation.

BackgroundHepatitis B core-related antigen (HBcrAg) is a novel serum viral marker. Recent studies showed that its level correlates with the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to evaluate the accuracy of serum HBsAg and HBcrAg levels at baseline to predict HCC.Methods1400 CHB patients who received nucleos(t)ide analogues (NA) treatment since December 2005 were included. Their stored serum samples at baseline were retrieved to measure HBsAg and HBcrAg levels. The primary endpoint was the cumulative incidence of HCC.Results85 (6.1%) patients developed HCC during a mean (± SD) follow-up duration of 45 ± 20 months. Serum HBcrAg level above 2.9 log10 U/mL at baseline was an independent factor for HCC in hepatitis B e antigen (HBeAg)-negative patients by multivariable analysis (adjusted hazard ratio 2.13, 95% CI 1.10–4.14, P = 0.025). HBcrAg above 2.9 log10 U/mL stratified the risk of HCC in HBeAg-negative patients with high PAGE-B score (P = 0.024 by Kaplan–Meier analysis), and possibly in cirrhotic patients (P = 0.08). Serum HBsAg level did not show any correlation with the risk of HCC in all patients or any subgroups.ConclusionSerum HBcrAg level predicts the risk of HCC accurately in NA-treated HBeAg-negative CHB patients.

Immunotherapy has dramatically improved the survival of patients with advanced or metastatic malignancies. Recent studies suggest that immunotherapy may increase the risk of hepatitis, whereas it may also induce functional cure of chronic hepatitis B virus (HBV) infection. We evaluated the incidence of hepatitis flare, HBV reactivation, hepatitis B surface antigen (HBsAg) seroclearance or seroreversion in patients with current or past HBV infection who had received immunotherapy. This was a territory-wide observational cohort study in Hong Kong. We identified patients through electronic medical records based on the prescriptions of immune checkpoint inhibitors from July 1, 2014, to December 31, 2019. Patients who were HBsAg positive or HBsAg negative with results for antibody to hepatitis B surface or core antigen (anti-HBs or anti-HBc) were included. A total of 990 patients (397 HBsAg-positive, 593 HBsAg-negative with 482 anti-HBc and/or anti-HBs positive, and 111 both anti-HBc and anti-HBs negative) were identified. All of HBsAg-positive and 15.9% HBsAg-negative patients were put on oral antiviral treatment. Hepatitis flare (alanine aminotransferase >2 times of the upper limit of normal) occurred in 39.3% HBsAg-positive and 30.4% HBsAg-negative patients. High baseline alanine aminotransferase and combination of immunotherapy increased the risk of hepatitis. HBV reactivation (≥2 log increase in HBV DNA from baseline) occurred in 2 HBsAg-positive patients; HBsAg seroclearance and seroreversion was observed in 1 HBsAg-positive and 1 HBsAg-negative patient, respectively (<1%). Hepatitis flare occurs in approximately 40% of HBsAg-positive patients and 30% of HBsAg-negative patients during immunotherapy. HBV reactivation, HBsAg seroclearance, and HBsAg seroreversion are rare. Current or past HBV infection has no impact on the emergence of hepatic flare associated with immunotherapy.

Liver stiffness measurement (LSM) by transient elastography (TE) has been shown to predict outcomes in patients with liver disease. While controlled attenuation parameter (CAP) measurement can accurately quantify hepatic steatosis, its prognostic value is unknown. We aim to determine if CAP is predictive for liver-related events (LRE), non-hepatocellular carcinoma (HCC) cancers, and cardiovascular events (CVE). Consecutive patients with both a reliable LSM and ≥10 successful CAP measurements by TE from August 2012 to March 2016 were included in the analysis. LRE were defined as HCC or hepatic decompensation. CVE were defined as acute coronary syndrome (ACS), cerebrovascular accident (CVA), or coronary intervention (stenting or bypass). Of the 5,848 patients that were examined, 4,282 (56.7% male, median age 57 years) had adequate follow-up, reliable LSM (median 6.1 kPa), and ≥10 CAP measurements (median 250 dB/m). Indications for TE were: suspected non-alcoholic fatty liver disease (NAFLD) (40.7%), hepatitis B (HBV) (37.0%), hepatitis C (2.9%), and others (19.4%). During 8,540 patient-years of follow-up, there were 45 patients with LRE (34 HCC, 33 decompensations), 73 with newly diagnosed non-HCC cancers, and 65 with CVE (27 ACS, 25 CVA, and 35 coronary interventions). CAP did not predict LRE, non-HCC cancer, or CVE on univariate analysis. On multivariate analysis, LSM, male sex, platelet count, serum albumin, and HBV etiology independently predicted LRE; age was the only independent predictor of non-HCC cancer; while age, fasting blood glucose, total cholesterol, and creatinine predicted for CVE. Subgroup analyses of viral hepatitis and NAFLD patients revealed similar results. Neither the presence nor the severity of hepatic steatosis as measured by CAP predict LRE, cancer, or CVE in the short term.

ObjectivePatients with a history of Helicobacter pylori-negative idiopathic bleeding ulcers have a considerable risk of recurrent ulcer complications. We hypothesised that a proton pump inhibitor (lansoprazole) is superior to a histamine 2 receptor antagonist (famotidine) for the prevention of recurrent ulcer bleeding in such patients.DesignIn this industry-independent, double-blind, randomised trial, we recruited patients with a history of idiopathic bleeding ulcers. After ulcer healing, we randomly assigned (1:1) patients to receive oral lansoprazole 30 mg or famotidine 40 mg daily for 24 months. The primary endpoint was recurrent upper GI bleeding within 24 months, analysed in the intention-to-treat population as determined by an independent adjudication committee.ResultsBetween 2010 and 2018, we enrolled 228 patients (114 patients in each study group). Recurrent upper GI bleeding occurred in one patient receiving lansoprazole (duodenal ulcer) and three receiving famotidine (two gastric ulcers and one duodenal ulcer). The cumulative incidence of recurrent upper GI bleeding in 24 months was 0.88% (95% CI 0.08% to 4.37%) in the lansoprazole arm and 2.63% (95% CI 0.71% to 6.91%) in the famotidine arm (p=0.313; crude HR 0.33, 95% CI 0.03 to 3.16, p=0.336). None of the patients who rebled used aspirin, non-steroidal anti-inflammatory drugs or other antithrombotic drugs.ConclusionThis 2-year, double-blind randomised trial showed that among patients with a history of H. pylori-negative idiopathic ulcer bleeding, recurrent bleeding rates were comparable between users of lansoprazole and famotidine, although a small difference in efficacy cannot be excluded.Trial registration number NCT01180179; Results.

ObjectivesAntiviral treatment modifies the natural history of chronic hepatitis B (CHB)-related cirrhosis as reflected by improving Model for End-Stage Liver Disease (MELD) score over time. We evaluated the impact of on-treatment change of MELD score on clinical outcomes in patients with CHB-related cirrhosis.MethodsCirrhotic CHB patients who received entecavir and/or tenofovir disoproxil fumarate for at least 6 months in Hong Kong between 2005 and 2016 were identified. The primary outcome was all-cause mortality; secondary outcomes were hepatocellular carcinoma (HCC), and hepatic events including ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatorenal syndrome, hepatic encephalopathy, and liver transplantation.ResultsWe identified 1743 cirrhotic CHB patients. Their mean MELD score decreased from 12.3 ± 5.5 at baseline to 11.0 ± 4.7 at month 6. At a median (interquartile range) follow-up of 3.9 (1.9–6.0) years, 290 (16.6%) patients died; 201 (11.5%) developed HCC. Among 1140 patients without prior hepatic events, 150 (13.2%) developed hepatic events. Among 464 patients with baseline MELD score ≥15, the 6-year cumulative mortality was 72.8, 36.7, and 23.1% for unchanged or increased MELD score, 1–5 point improvement in MELD score, and >5 point improvement in MELD score at month 6, respectively (log-rank test, P < 0.001); the corresponding 6-year cumulative incidence of hepatic events was 52.7, 30.5, and 23.9% in the three subgroups (Gray’s test, P = 0.004). Patients with MELD score <15 at month 6 had lower risk of mortality and hepatic events (all P < 0.001).ConclusionsOn-treatment improvement of MELD score correlates with reduced risk of mortality and hepatic events in cirrhotic CHB patients.

The Baveno VII criteria are used in patients with liver cirrhosis to predict high-risk varices in patients with liver cirrhosis. Yet its use in patients with advanced hepatocellular carcinoma (HCC) has not been validated. HCC alone is accompanied with a higher variceal bleeding risk due to its association with liver cirrhosis and portal vein thrombosis. The use of systemic therapy in advanced HCC has been thought to further augment this risk. Upper endoscopy is commonly used to evaluate for the presence of varices before initiation of treatment with systemic therapy. Yet it is associated with procedural risks, waiting time and limited availability in some localities which may delay the commencement of systemic therapy. Our study successfully validated the Baveno VI criteria with a 3.5% varices needing treatment (VNT) missed rate, also with acceptable <5% VNT missed rates when considering alternative liver stiffness (LSM) and platelet cut-offs. The Baveno VII clinically significant portal hypertension rule-out criteria (LSM < 15 kPa and platelet >150 × 109/L) also revealed a low frequency (2%) of hepatic events, whilst the rule-in criteria (LSM > 25 kPa) was predictive of a higher proportion of hepatic events (14%). Therefore, our study has successfully validated the Baveno VII criteria as a non-invasive stratification of the risk of variceal bleeding and hepatic decompensation in the HCC population.

Background Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of cancers. We aimed to evaluate the incidence and prognostic impact of hepatic adverse events (AEs) in a territory‐wide cohort of patients who received ICIs. Methods Patients were identified from a territory‐wide database who received ICIs in 2014‐2018. Hepatic AEs were defined as any elevation of liver biochemistries including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels. Hepatic AEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results Total of 1480 patients were identified (mean age 60 years, male 65.5%) and the commonest malignancies being lung cancer (39.6%), liver cancer (16.5%), and gastrointestinal cancer (10.0%). Grade 1‐2 and grade 3‐4 hepatic AEs occurred in 41.3% and 14.9% of patients during ICI treatment, respectively. Patients with liver cancer had the highest rate of hepatic AEs (grade 1‐2:54.1%; grade 3‐4:32.8%). Among 711 patients with hepatic AEs, 383 (53.9%) had raised ALT/AST only, and 328 (46.1%) had concomitant raised ALT/AST and bilirubin levels. In the whole cohort, median overall survival of patients without any hepatic AEs, grade 1‐2 and grade 3‐4 hepatic AEs during ICI treatment was 9.0 months, 7.2 months, and 3.3 months (P < .001), respectively. Similar results on overall survival were obtained among different types of cancers. Conclusions Hepatic AEs occur in more than half of patients receiving ICIs for cancer treatment, with approximately 15% being grade 3‐4 AEs. Occurrence of hepatic AEs is associated with worse prognosis. Hepatic adverse events are common and may occur in more than half of patients receiving immune checkpoint inhibitors for cancer treatment. Severe hepatic adverse events of grade 3‐4 occur in 15% and are associated with worse prognosis.

BackgroundLiver injury in patients with coronavirus disease 2019 (COVID-19) is common and prognostic. Direct viral tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for angiotensin-converting enzyme 2 receptors in hepatocytes may be one of the mechanisms of liver injury. We aimed to determine the role of viral persistence of SARS-CoV-2, based on cycle threshold (Ct) value, in liver injury in COVID-19. MethodsThis was a territory-wide retrospective cohort study of all public hospitals in Hong Kong. Laboratory-confirmed COVID-19 was identified. Serial liver biochemistries and Ct values of SARS-CoV-2 RNA were analyzed. ResultsWe identified 7622 COVID-19 patients (mean age, 47 years; 48.2% male) diagnosed from March 24 to January 1, 2021, who had serial liver biochemistries and Ct values. A total of 1363 (17.9%) COVID-19 patients had alanine transferase (ALT)/aspartate aminotransferase (AST) elevations with 2 temporal patterns—early (within first 14 days of symptom onset) and late (>14 days from symptom onset). COVID-19 patients with ALT/AST elevations had a lower Ct value at admission (23 vs 25; P < .001), day 5 (24 vs 26; P < .001), and day 20 (31 vs 32; P < .001) after admission, compared with those without ALT/AST elevations. COVID-19 patients with ALT/AST elevations had a longer duration from first positive to first negative reverse transcription polymerase chain reaction test for SARS-CoV-2 (13 vs 9 days; P < .001). ALT/AST elevation and presence of diabetes were independent risk factors of viral persistence. ConclusionsLiver injury in COVID-19 is linked to a higher SARS-CoV-2 viral load during the early phase of infection, signifying a possible direct viral injury to the liver. Prolonged viral persistence of SARS-CoV-2 is associated with liver injury.

The benefit of colonoscopy and/or polypectomy for colorectal cancer (CRC) prevention in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear. We aimed to estimate the incidence rate of CRC in patients with NAFLD who had and had not undergone colonoscopy. We conducted a retrospective territory‐wide cohort study for patients aged over 40 years with NAFLD identified with the International Classification of Diseases, Ninth Revision, Clinical Modification codes between January 1, 2000, and December 31, 2014. Patients were followed until CRC diagnosis, death, or December 31, 2017. We estimated CRC incidence and standardized incidence ratio (SIR) using the general population of Hong Kong as reference. We included 8,351 patients with NAFLD in the final analysis (median age, 56.2 years; interquartile ratio [IQR], 49.2‐65.3 years; 45.4% male; median follow‐up, 7.4 years; IQR, 5.4‐9.6 years). Compared with the general population, patients with NAFLD who had not undergone colonoscopy had a higher incidence of CRC (SIR, 2.20; 95% confidence interval [CI], 1.64‐2.88; P < 0.001). Patients with NAFLD who had undergone colonoscopy had a lower incidence of CRC (SIR, 0.54; 95% CI, 0.37‐0.75; P < 0.001), especially among those aged above 50 years or with diabetes mellitus (DM). Patients with NAFLD with a high fibrosis‐4 (FIB‐4) score (>2.67) had a significantly higher risk of CRC after adjusting for demographic and metabolic factors. Conclusion: Patients with NAFLD who had undergone colonoscopy had a lower incidence of CRC than the general population, especially among those aged ≥50 years or with DM. A high FIB‐4 index was associated with a higher risk of CRC.