Angel Mei-Ling Chim

Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years

Background Patients with non-alcoholic steatohepatitis (NASH) have increased mortality and liver-related complications. In contrast, simple steatosis is considered benign and non-progressive. Objective To investigate disease progression in patients with different degrees of non-alcoholic fatty liver disease (NAFLD) activity. Design Prospective longitudinal hospital-based cohort study. Patients Fifty-two patients (age 44±9 years) with biopsy-proven NAFLD had liver biopsies repeated at month 36. Results Among 13 patients with simple steatosis at baseline, 2 (15%) had a normal liver at month 36, 3 (23%) continued to have simple steatosis, 5 (39%) developed borderline NASH and 3 (23%) developed NASH. Among 22 patients with borderline NASH at baseline, 4 (18%) had simple steatosis and 13 (59%) had borderline NASH at month 36, while 5 (23%) developed NASH. Among 17 patients with NASH at baseline, 10 (59%) continued to have NASH and 6 (35%) had borderline NASH at month 36. Only 1 (6%) patient regressed to simple steatosis. Overall, 14 (27%) patients had fibrosis progression, 25 (48%) had static disease, and 13 (25%) had fibrosis regression. Reduction in body mass index and waist circumference was independently associated with non-progressive disease activity and fibrosis. The baseline serum levels and month 36 changes in adiponectin, tumour necrosis factor α, interleukin 6 and leptin were not associated with disease progression. Serum cytokeratin-18 fragment level reflected disease activity and its change correlated with the change in NAFLD activity score (R=0.51, p<0.001). Conclusions Patients with simple steatosis may still develop NASH and fibrosis progression. Weight reduction is associated with non-progressive disease. All patients with NAFLD should undergo periodic assessment and lifestyle modification.

Prevalence of non-alcoholic fatty liver disease and advanced fibrosis in Hong Kong Chinese: a population study using proton-magnetic resonance spectroscopy and transient elastography

Objective Knowledge of the epidemiology of non-alcoholic fatty liver disease (NAFLD) is incomplete because liver biopsy cannot be performed on the general population to assess disease severity. New non-invasive tests allow accurate and safe assessment in healthy individuals. The aim of this study was to examine the prevalence of NAFLD and advanced fibrosis in the general Hong Kong Chinese population. Methods Subjects were recruited from the community by random selection from the government census database. Liver fat and fibrosis were assessed by proton-magnetic resonance spectroscopy and transient elastography, respectively. Results Overall, 264 of 922 (28.6%) subjects had intrahepatic triglyceride content ≥5%. Excluding 12 subjects with significant alcohol consumption, the population prevalence of NAFLD was 27.3% (95% CI 24.5% to 30.2%). Each component of the metabolic syndrome increased the risk of fatty liver in a dose-dependent manner (prevalence of 4.5% in subjects without any component and 80.0% in those with all five components). 8 (3.7%) patients with fatty liver had liver stiffness ≥9.6 kPa, a level suggestive of advanced fibrosis. Body mass index and alanine aminotransferase level were independent factors associated with liver stiffness. Together with other clinical prediction scores, the estimated prevalence of advanced fibrosis in patients with fatty liver in the community was <10%. Compared with non-drinkers, modest drinkers (<10 g per day) did not have higher risk of fatty liver after adjustment for demographic and metabolic factors. The liver stiffness was 4.7±1.9 kPa in modest drinkers and 4.6±1.7 kPa in non-drinkers (p=0.54). Conclusion NAFLD is found in over a quarter of the general adult Chinese population, but the proportion of patients with advanced fibrosis is low. Modest alcohol consumption does not increase the risk of fatty liver or liver fibrosis.

Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease

Objective Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is associated with cardiovascular risk. The aim of this study was to determine the role of fatty liver in predicting coronary artery disease and clinical outcomes in patients undergoing coronary angiogram. Methods This was a prospective cohort study carried out in a University hospital. Consecutive patients who underwent coronary angiogram had ultrasound screening for fatty liver. Significant cardiovascular disease was defined as ≥50% stenosis in at least one coronary artery. The primary outcome was a composite end point comprising cardiovascular deaths, non-fatal myocardial infarction and the need for further coronary intervention during prospective follow-up. Results Among 612 recruited patients, 356 (58.2%) had fatty liver by ultrasonography, 318 (52.0%) had elevated serum alanine aminotransferase and 465 (76.0%) had significant coronary artery disease. Coronary artery disease occurred in 84.6% of patients with fatty liver and 64.1% of those without fatty liver (p<0.001). After adjusting for demographic and metabolic factors, fatty liver (adjusted OR 2.31; 95% CI 1.46 to 3.64) and alanine aminotransferase level (adjusted OR 1.01; 95% CI 1.00 to 1.02) remained independently associated with coronary artery disease. At a mean follow-up of 87±22 weeks, 30 (10.0%) patients with fatty liver and 18 (11.0%) patients without fatty liver reached the composite clinical end point (p=0.79). Conclusions In patients with clinical indications for coronary angiogram, fatty liver is associated with coronary artery disease independently of other metabolic factors. However, fatty liver cannot predict cardiovascular mortality and morbidity in patients with established coronary artery disease.

Identification of Chronic Hepatitis B Patients without Significant Liver Fibrosis by a Simple Noninvasive Predictive Model

OBJECTIVE:Histological assessment of liver fibrosis is important in the management of chronic hepatitis B (CHB) infection but poorly accepted by patients because of its invasiveness. The aim of this study was to develop a noninvasive model to assess liver fibrosis in CHB patients using clinical and routine laboratory data.PATIENTS AND METHODS:This was a retrospective study on 235 treatment-naïve viremic CHB patients. Univariate analysis of data from the training cohort (n = 150) followed by multivariate logistic regression were performed to identify independent predictors of significant fibrosis and generate predictive models. The models were validated with the remaining patients or validation cohort (n = 85) and by receiver operating characteristics (ROC) analysis.RESULTS:Body mass index (BMI), platelet count, serum albumin, and total bilirubin levels were identified as independent predictors of bridging fibrosis or cirrhosis (Ishak stage 3–6). ROC analysis was performed using the predictive probabilities derived from the regression models. The area under the ROC curve of the best model was 0.803 (95% CI: 0.729–0.878) for the training cohort, 0.765 (95% CI: 0.644–0.885) for the validation cohort, and 0.791 (95% CI: 0.728–0.854) for the entire cohort. Using the low cut-off probability of 0.15, significant fibrosis could be excluded in 83 patients of the total patient population (negative predictive value 0.92).CONCLUSIONS:Our noninvasive model comprising BMI and three routine laboratory tests was accurate in predicting absence of significant fibrosis. Application of this model could provide useful additional information on the stage of disease, guide future management decisions, and potentially decrease the need for liver biopsy in some CHB patients.

High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis

Objective Non-alcoholic fatty liver disease (NAFLD) affects 20–40% of the general adult population. Due to shared risk factors, it is postulated that NAFLD patients have an increased risk of colorectal neoplasm and should be a target group for screening. The aim of this study was to examine the prevalence of colorectal neoplasm in NAFLD patients and the risk of colorectal neoplasm in relation to the severity of NAFLD histology. Design Cross-sectional study. Setting University hospital with case recruitment from the community and clinics. Patients Subjects aged 40–70 years were recruited for colonoscopic screening from two study cohorts: (1) community subjects; and (2) consecutive patients with biopsy proven NAFLD. In the community cohort, hepatic fat was measured by proton-magnetic resonance spectroscopy. Main outcome measures Prevalence of colorectal adenomas. Advanced colorectal neoplasm was defined as cancer or adenomas with villous architecture or high grade dysplasia. Results NAFLD patients (N=199) had a higher prevalence of colorectal adenomas (34.7% vs 21.5%; p=0.043) and advanced neoplasms (18.6% vs 5.5%; p=0.002) than healthy controls (N=181). Thirteen of 29 (45%) NAFLD patients with advanced neoplasms had isolated lesions in the right sided colon. Among patients with biopsy proven NAFLD, patients with non-alcoholic steatohepatitis (N=49) had a higher prevalence of adenomas (51.0% vs 25.6%; p=0.005) and advanced neoplasms (34.7% vs 14.0%; p=0.011) than those with simple steatosis (N=86). After adjusting for demographic and metabolic factors, non-alcoholic steatohepatitis remained associated with adenomas (adjusted OR 4.89, 95% CI 2.04 to 11.70) and advanced neoplasms (OR 5.34, 95% CI 1.92 to 14.84). In contrast, the prevalence of adenomas and advanced neoplasms was similar between patients with simple steatosis and control subjects. Conclusions Non-alcoholic steatohepatitis is associated with a high prevalence of colorectal adenomas and advanced neoplasms. The adenomas are found more commonly in the right sided colon. Colorectal cancer screening is strongly indicated in this high risk group.

Quantitative Elastography of Liver Fibrosis and Spleen Stiffness in Chronic Hepatitis B Carriers: Comparison of Shear-Wave Elastography and Transient Elastography with Liver Biopsy Correlation

PURPOSE To document utility of shear-wave (SW) elastography for assessing liver fibrosis in chronic hepatitis B and to compare its performance with that of transient elastography. MATERIALS AND METHODS Ethics committee approved the study, and informed consent was obtained. Patients with liver biopsy correlation (n = 226) and healthy patients (n = 171) were analyzed. Results of SW elastography of liver, SW elastography of spleen, and transient elastography of liver were compared and correlated according to METAVIR scores. Areas under the receiver operating characteristic curve (AUCs), binary logistic regression, and Delong test were used. RESULTS AUC for SW elastography of liver, transient elastography of liver, and SW elastography of spleen was, respectively, 0.86, 0.80, and 0.81 for fibrosis (≥ F1 stage); 0.88, 0.78, and 0.82 for moderate fibrosis (≥ F2 stage); 0.93, 0.83, and 0.83 for severe fibrosis (≥ F3 stage); and 0.98, 0.92, and 0.84 for cirrhosis (F4 stage). SW elastography of liver showed significantly higher accuracy than transient elastography of liver and SW elastography of spleen in all fibrosis stages (P = .01-.04). SW elastography of spleen showed similar accuracy with transient elastography of liver (P = .21-.99). Combination SW elastography of liver and SW elastography of spleen to predict fibrosis staging showed diagnostic accuracy not further improved compared with SW elastography of liver alone (similar AUC; ≥ F1, P = .87; ≥ F2, P = .81; ≥ F3, P = .84; ≥ F4, P = .88). SW elastography of liver had higher successful rate than transient elastography of liver (98.9% vs 89.6%). Prevalence of discordance in at least two stages with liver histologic staging was 10.2% (23 of 226) for SW elastography of liver and 28.2% (58 of 206) for SW elastography of spleen. CONCLUSION SW elastography provides more accurate correlation of liver elasticity with liver fibrosis stage compared with transient elastography, especially in identification of stage F2 or greater.

Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers.

BACKGROUND & AIMS The diagnosis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is limited by the need for liver biopsy. We aimed at testing the accuracy of cytokeratin-18 fragment (CK-18), adipocyte fatty acid binding protein (AFABP) and fibroblast growth factor 21 (FGF21) for the diagnosis of NAFLD and NASH. METHODS 146 patients with biopsy-proven NAFLD and 74 age- and gender-matched healthy controls were included. Serum CK-18, AFABP and FGF21 levels were determined by enzyme-linked immunosorbent assay. RESULTS Serum CK-18, AFABP, and FGF21 increased in a stepwise fashion in control subjects (median 103 U/L, 15.4 ng/ml, and 104 pg/ml), patients with non-NASH NAFLD (263 U/L, 18.9 ng/ml, and 249 pg/ml) and NASH (418 U/L, 19.4 ng/ml, and 354 pg/ml) (p<0.001, 0.060, and 0.016, respectively). The area under receiver-operating characteristics curve to diagnose NAFLD and NASH was 0.91 and 0.70 for CK-18, 0.66 and 0.59 for AFABP, and 0.84 and 0.62 for FGF21. At cut-offs of 203 and 670 U/L, CK-18 had 71% negative predictive value (NPV) and 77% positive predictive value (PPV) to exclude and diagnose NASH. A 2-step approach measuring CK-18 followed by FGF21 further improved the NPV to 74% and PPV to 82%. In a validation cohort of 51 patients with paired liver biopsies, the NPV and PPV of the 2-step approach were 67% and 78%, respectively. CONCLUSIONS CK-18 is the most accurate biomarker for NAFLD and NASH. A two-step approach using CK-18 and FGF21 further improves the accuracy in diagnosing NASH.

Community-based lifestyle modification programme for non-alcoholic fatty liver disease: A randomized controlled trial

BACKGROUND & AIMS Healthy lifestyle is the most important management of non-alcoholic fatty liver disease (NAFLD). This study aimed at assessing the efficacy of a community-based lifestyle modification programme in the remission of NAFLD. METHODS This was a parallel group, superiority, randomized controlled trial. 154 adults with NAFLD identified during population screening were randomized to participate in a dietitian-led lifestyle modification programme at 2 community centres or receive usual care for 12 months. The primary outcome was remission of NAFLD at month 12 as evidenced by intrahepatic triglyceride content (IHTG) of less than 5% by proton-magnetic resonance spectroscopy. RESULTS 74 patients in the intervention group and 71 patients in the control group completed all study assessments. In an intention-to-treat analysis of all 154 patients, 64% of the patients in the intervention group and 20% in the control group achieved remission of NAFLD (difference between groups 44%; 95% CI 30-58%; p<0.001). The mean (SD) changes in IHTG from baseline to month 12 were -6.7% (6.1%) in the intervention group and -2.1% (6.4%) in the control group (p<0.001). Body weight decreased by 5.6 (4.4) kg and 0.6 (2.5) kg in the two groups, respectively (p<0.001). While 97% of patients with weight loss of more than 10% had remission of NAFLD, 41% of those with weight loss of 3.0-4.9% could also achieve the primary outcome. CONCLUSIONS The community-based lifestyle modification programme is effective in reducing and normalizing liver fat in NAFLD patients.

Hepatitis B virus infection and fatty liver in the general population.

BACKGROUND & AIMS In animal studies, expression of hepatitis B virus (HBV) proteins causes hepatic steatosis. We aimed to study the prevalence of fatty liver in people with and without HBV infection in the general population. METHODS We performed a cross-sectional population study in Hong Kong Chinese. Intrahepatic triglyceride content (IHTG) was measured by proton-magnetic resonance spectroscopy. RESULTS One thousand and thirteen subjects (91 HBV patients and 922 controls) were recruited. The median IHTG was 1.3% (0.2-33.3) in HBV patients and 2.1% (0-44.2) in controls (p <0.001). Excluding subjects with significant alcohol consumption, the prevalence of nonalcoholic fatty liver disease was 13.5% (95% confidence interval [CI] 6.4%, 20.6%) in HBV patients and 28.3% (95% CI 25.3%, 31.2%) in controls (p=0.003). The fatty liver prevalence differed in HBV patients and controls aged 40-59 years but was similar in those aged 60 years or above. After adjusting for demographic and metabolic factors, HBV infection remained an independent factor associated with lower risk of fatty liver (adjusted odds ratio 0.42; 95% CI 0.20, 0.88; p=0.022). HBV patients also had a lower prevalence of metabolic syndrome (11.0% vs. 20.2%; p=0.034), but the difference was mainly attributed to lower triglyceride levels. Among HBV patients, viral genotypes, HBV DNA level and hepatitis B e antigen status were not associated with fatty liver. CONCLUSIONS HBV infection is associated with a lower prevalence of fatty liver, hypertriglyceridemia and metabolic syndrome. Viral replication may affect lipid metabolism and this warrants further studies.

Molecular Characterization of the Fecal Microbiota in Patients with Nonalcoholic Steatohepatitis - A Longitudinal Study

Background The human gut microbiota has profound influence on host metabolism and immunity. This study characterized the fecal microbiota in patients with nonalcoholic steatohepatitis (NASH). The relationship between microbiota changes and changes in hepatic steatosis was also studied. Methods Fecal microbiota of histology-proven NASH patients and healthy controls was analyzed by 16S ribosomal RNA pyrosequencing. NASH patients were from a previously reported randomized trial on probiotic treatment. Proton-magnetic resonance spectroscopy was performed to monitor changes in intrahepatic triglyceride content (IHTG). Results A total of 420,344 16S sequences with acceptable quality were obtained from 16 NASH patients and 22 controls. NASH patients had lower fecal abundance of Faecalibacterium and Anaerosporobacter but higher abundance of Parabacteroides and Allisonella. Partial least-square discriminant analysis yielded a model of 10 genera that discriminated NASH patients from controls. At month 6, 6 of 7 patients in the probiotic group and 4 of 9 patients in the usual care group had improvement in IHTG (P = 0.15). Improvement in IHTG was associated with a reduction in the abundance of Firmicutes (R2 = 0.4820, P = 0.0028) and increase in Bacteroidetes (R2 = 0.4366, P = 0.0053). This was accompanied by corresponding changes at the class, order and genus levels. In contrast, bacterial biodiversity did not differ between NASH patients and controls, and did not change with probiotic treatment. Conclusions NASH patients have fecal dysbiosis, and changes in microbiota correlate with improvement in hepatic steatosis. Further studies are required to investigate the mechanism underlying the interaction between gut microbes and the liver.