Hepatocyte apoptosis fragment product cytokeratin-18 M30 level and non-alcoholic steatohepatitis risk diagnosis: an international registry study / 中华医学杂志(英文版)

BACKGROUND@#Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.@*METHODS@#Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL).@*RESULTS@#A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69-1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension ( P  < 0.001, P  = 0.026 and P  = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714-0.787), and CK-18 M30 at Youden's index maximum was 275.7 U/L. Both sensitivity (55% [52%-59%]) and positive predictive value (59%) were not ideal.@*CONCLUSION@#This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.

Calculated parameters for the diagnosis of Wilson disease

INTRODUCTION@#The diagnosis of Wilson disease (WD) is plagued by biochemical and clinical uncertainties. Thus, calculated parameters have been proposed. This study aimed to: (a) compare the diagnostic values of non-caeruloplasmin copper (NCC), NCC percentage (NCC%), copper-caeruloplasmin ratio (CCR) and adjusted copper in WD; and (b) derive and evaluate a discriminant function in diagnosing WD.@*METHODS@#A total of 213 subjects across all ages who were investigated for WD were recruited. WD was confirmed in 55 patients, and the rest were WD free. Based on serum copper and caeruloplasmin values, NCC, NCC%, CCR and adjusted copper were calculated for each subject. A function was derived using discriminant analysis, and the cut-off value was determined through receiver operating characteristic analysis. Classification accuracy was found by cross-tabulation.@*RESULTS@#Caeruloplasmin, total copper, NCC, NCC%, CCR, adjusted copper and discriminant function were significantly lower in WD compared to non-WD. Discriminant function showed the best diagnostic specificity (99.4%), sensitivity (98.2%) and classification accuracy (99.1%). Caeruloplasmin levels <0.14 g/L showed higher accuracy than the recommended 0.20 g/L cut-off value (97.7% vs. 87.8%). Similarly, molar NCC below the European cut-off of 1.6 umol/L showed higher accuracy than the American cut-off of 3.9 umol/L (80.3% vs. 59.6%) (P < 0.001). NCC%, mass NCC, CCR and adjusted copper showed poorer performances.@*CONCLUSION@#Discriminant function differentiates WD from non-WD with excellent specificity, sensitivity and accuracy. Performance of serum caeruloplasmin <0.14 g/L was better than that of <0.20 g/L. NCC, NCC%, CCR and adjusted copper are not helpful in diagnosing WD.

Comparison between obese and non-obese nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver conditions that are characterized by excess accumulation of fat in the liver, and is diagnosed after exclusion of significant alcohol intake and other causes of chronic liver disease. In the majority of cases, NAFLD is associated with overnutrition and obesity, although it may be also found in lean or non-obese individuals. It has been estimated that 19.2% of NAFLD patients are lean and 40.8% are non-obese. The proportion of patients with more severe liver disease and the incidence of all-cause mortality, liver-related mortality, and cardiovascular mortality among non-obese and obese NAFLD patients varies across studies and may be confounded by selection bias, underestimation of alcohol intake, and unaccounted weight changes over time. Genetic factors may have a greater effect towards the development of NAFLD in lean or non-obese individuals, but the effect may be less pronounced in the presence of strong environmental factors, such as poor dietary choices and a sedentary lifestyle, as body mass index increases in the obese state. Overall, non-invasive tests, such as the Fibrosis-4 index, NAFLD fibrosis score, and liver stiffness measurement, perform better in lean or non-obese patients compared to obese patients. Lifestyle intervention works in non-obese patients, and less amount of weight loss may be required to achieve similar results compared to obese patients. Pharmacological therapy in non-obese NAFLD patients may require special consideration and a different approach compared to obese patients.

Barcelona Clinic Liver Cancer and Hong Kong Liver Cancer staging systems for prediction of survival among Hepatocellular Carcinoma patients

@#Introduction: We aimed to compare the Barcelona Clinic Liver Cancer (BCLC) and Hong Kong Liver Cancer (HKLC) staging systems. Materials and Methods: This is a retrospective study on patients with newly diagnosed hepatocellular carcinoma (HCC) at the University Malaya Medical Centre between 2011 and 2014. Survival times were analysed using the KaplanMeier procedure and comparison between groups was done using the log rank test. Results: The data of 190 patients was analysed. Chronic hepatitis B was the most common aetiology for HCC (43.7%), but a large proportion was cryptogenic or non-alcoholic steatohepatitis-related (41.6%). Only 11.1% were diagnosed early (BCLC Stage 0-A) while majority were diagnosed at an intermediate stage (BCLC Stage B, 53.7%). The median survival rate was significantly different between the different groups when either of the staging systems was used (p<0.05 for all comparisons). However, the two staging systems lacked agreement (weighted kappa 0.519, 95%CI: 0.449, 0.589) with significant difference in median survival rates between BCLC Stage A and HKLC Stage 2, and between BCLC Stage C and HKLC Stage 4. Conclusion: Both staging systems were able to stratify patients according to survival, but they only had moderate agreement with significant differences observed in two groups of the staging systems.

Loss-of-function HSD17B13 variants, non-alcoholic steatohepatitis and adverse liver outcomes: Results from a multi-ethnic Asian cohort

Background/Aims@#17β-hydroxysteroid dehydrogenase 13 (HSD17B13) variants were recently reported to have significantly lower odds of non-alcoholic fatty liver disease (NAFLD). This is a two-part study that aimed to evaluate the association of HSD17B13 variants with NAFLD and its histological severity, and to identify the association of the variants with clinical outcomes in a cohort of biopsy-proven NAFLD patients. @*Methods@#Consecutive biopsy-proven NAFLD patients and controls without fatty liver were recruited for this study between 2009 and 2014. Genotyping for HSD17B13 variants was performed using rhAmp assays. A total of 165 patients with NAFLD were monitored up until August 2019. Clinical outcomes were recorded. @*Results@#HSD17B13 rs72613567 TA allele and rs6834314 G allele were associated with lower odds of non-alcoholic steatohepatitis (NASH) in the overall cohort and among ethnic Chinese, but not among ethnic Malays or Indians (P<0.05). During a mean follow-up of 89 months, 32 patients (19.4%) experienced at least one clinical outcome (cardiovascular events, n=22; liver-related complications, n=6; extra-hepatic malignancy, n=5; and mortality, n=6). The rs72613567 homozygous TA allele and the rs6834314 homozygous G allele were independently associated with a lower incidence of liver-related complications (hazard ratio [HR], 0.004; 95% confidence interval [CI], 0.00–0.64; P=0.033 and HR, 0.01; 95% CI, 0.00–0.97; P=0.048, respectively) and were associated with lower grade of hepatocyte ballooning among the ethnic Chinese. @*Conclusion@#HSD17B13 rs72613567 and rs6834314 variants were inversely associated with NAFLD and NASH, and were associated with lower incidence of adverse liver outcomes in a cohort of multi-ethnic Asian patients with NAFLD.

Loss-of-function HSD17B13 variants, non-alcoholic steatohepatitis and adverse liver outcomes: Results from a multi-ethnic Asian cohort

Background/Aims@#17β-hydroxysteroid dehydrogenase 13 (HSD17B13) variants were recently reported to have significantly lower odds of non-alcoholic fatty liver disease (NAFLD). This is a two-part study that aimed to evaluate the association of HSD17B13 variants with NAFLD and its histological severity, and to identify the association of the variants with clinical outcomes in a cohort of biopsy-proven NAFLD patients. @*Methods@#Consecutive biopsy-proven NAFLD patients and controls without fatty liver were recruited for this study between 2009 and 2014. Genotyping for HSD17B13 variants was performed using rhAmp assays. A total of 165 patients with NAFLD were monitored up until August 2019. Clinical outcomes were recorded. @*Results@#HSD17B13 rs72613567 TA allele and rs6834314 G allele were associated with lower odds of non-alcoholic steatohepatitis (NASH) in the overall cohort and among ethnic Chinese, but not among ethnic Malays or Indians (P<0.05). During a mean follow-up of 89 months, 32 patients (19.4%) experienced at least one clinical outcome (cardiovascular events, n=22; liver-related complications, n=6; extra-hepatic malignancy, n=5; and mortality, n=6). The rs72613567 homozygous TA allele and the rs6834314 homozygous G allele were independently associated with a lower incidence of liver-related complications (hazard ratio [HR], 0.004; 95% confidence interval [CI], 0.00–0.64; P=0.033 and HR, 0.01; 95% CI, 0.00–0.97; P=0.048, respectively) and were associated with lower grade of hepatocyte ballooning among the ethnic Chinese. @*Conclusion@#HSD17B13 rs72613567 and rs6834314 variants were inversely associated with NAFLD and NASH, and were associated with lower incidence of adverse liver outcomes in a cohort of multi-ethnic Asian patients with NAFLD.

Hepatitis B virus infection among children of hepatitis B surface antigen positive mothers in a Malaysian hospital

transmission of hepatitis B virus (HBV) infection amongchildren of hepatitis B surface antigen (HBsAg) positivemothers in Malaysia. Methods: This is a cross-sectional study of all the childrenof HBsAg-positive mothers who delivered at the Universityof Malaya Medical Centre between 1993 and 2000. Results: A total of 60 HBsAg-positive mothers and their 154children participated in the study. HBsAg was detected infour children (2.6%) while IgG antibody to the hepatitis Bcore antigen (anti-HBc IgG) was detected in seventeenchildren (11.0%). The mother’s age at childbirth wassignificantly lower in the children with detectable HBsAg(22.5±6.1 years vs. 29.7±4.5 years, p=0.043) and anti-HBc IgG(26.6±6.1 years vs. 30.0±4.3 years, p=0.004). Children born inthe 1980s were significantly more likely to have detectableHBsAg (18.8% vs. 0.7%, p=0.004) and anti-HBc IgG (37.5%vs. 8.0%, p=0.000) compared with those born later. Allchildren with detectable HBsAg were born via spontaneousvaginal delivery, and hepatitis B immunoglobulin was eithernot given or the administration status was unknown. Themajority of mothers with chronic HBV infection (70.4%) werenot under any regular follow-up for their chronic HBVinfection and the main reason was the lack of awareness ofthe need to do so (47.4%). Conclusion: Transmission of HBV infection among childrenof HBsAg-positive mothers in Malaysia is low. However,attention needs to be given to the high rate of HBsAg-positive mothers who are not on any regular follow-up.

A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Silymarin is a complex mixture of 6 major flavonolignans and other minor polyphenolic compounds derived from the milk thistle plant Silybum marianum; it has shown antioxidant, anti-inflammatory and antifibrotic effects, and may be useful in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to study the efficacy of silymarin in patients with nonalcoholic steatohepatitis (NASH)-the more severe form of NAFLD. METHODS: We performed a randomized, double-blind, placebo-controlled trial of consecutive adults with biopsy-proven NASH and a NAFLD activity score (NAS) of 4 or more at a tertiary care hospital in Kuala Lumpur, Malaysia, from November 2012 through August 2014. Patients were randomly assigned to groups given silymarin (700 mg; n = 49 patients) or placebo (n = 50 patients) 3 times daily for 48 weeks. After this 48-week period, liver biopsies were repeated. The primary efficacy outcome was a decrease of 30% or more in NAS; findings from 48-week liver biopsies were compared with those from the baseline biopsy. Secondary outcomes included changes in steatosis, lobular inflammation, hepatocyte ballooning, NAS and fibrosis score, and anthropometric measurements, as well as glycemic, lipid, and liver profiles and liver stiffness measurements. RESULTS: The percentage of patients achieving the primary efficacy outcome did not differ significantly between the groups (32.7% in the silymarin group vs 26.0% in the placebo group; P = .467). A significantly higher proportion of patients in the silymarin group had reductions in fibrosis based on histology (reductions of 1 point or more; 22.4%) than did the placebo group (6.0%; P = .023), and based on liver stiffness measurements (decrease of 30% or more; 24.2%) than did the placebo group (2.3%; P = .002). The silymarin group also had significant reductions in mean aspartate aminotransferase to platelet ratio index (reduction of 0.14, P = .011 compared with baseline), fibrosis-4 score (reduction of 0.20, P = .041 compared with baseline), and NAFLD fibrosis score (reduction of 0.30, P < .001 compared with baseline); these changes were not observed in the placebo group (reduction of 0.07, P = .154; increase of 0.18, P = .389; and reduction of 0.05, P = .845, respectively). There was no significant difference between groups in number of adverse events; adverse events that occurred were not attributed to silymarin. CONCLUSIONS: In a randomized trial of 99 patients, we found that silymarin (700 mg, given 3 times daily for 48 weeks) did not reduce NAS scores by 30% or more in a significantly larger proportion of patients with NASH than placebo. Silymarin may reduce liver fibrosis but this remains to be confirmed in a larger trial. It appears to be safe and well tolerated. ClinicalTrials.gov: NCT02006498.

Enteropathy-associated T-cell lymphoma: An extremely rare cause of chronic diarrhoea

Chronic diarrhoea in tropical countries may be due to a myriad of causes from infective to non-infective. This case report illustrates the challenges faced in the investigation of a middle-age Chinese gentleman who presented with chronic diarrhoea and weight loss. The diagnosis of type II enteropathy-associated T-cell lymphoma (EATL) was finally made. The diagnosis of EATL was least suspected as the condition is almost unheard of in this part of the world. The epidemiology, presentation, diagnosis, management and prognosis of this rare condition are discussed.

Epidemiology of a fast emerging disease in the Asia-Pacific region: non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is rapidly increasing in the Asia-Pacific and affects up to 30 % of the general population. In younger children, prevalence has been reported to be between 2.1 and 4.5 %. The prevalence of NAFLD increases with increasing age. NAFLD is more prevalent in men than women, but this trend fades in older age group. NAFLD is one of the most common causes of raised serum ALT levels and the latter is closely related to the presence of features of metabolic syndrome. NAFLD may contribute to metabolic syndrome in a similar way as visceral adiposity and can be an early predictor of metabolic disorders. NAFLD increases the risk of developing diabetes mellitus and is closely related to degree of glucose intolerance. A significant proportion of patients with NAFLD have impaired glucose tolerance or diabetes mellitus but with normal fasting blood glucose, highlighting the importance of oral glucose tolerance test in NAFLD patients with normal fasting blood glucose. Besides liver-related complications, NAFLD has been associated with cardiovascular complications, hyperuricemia, gout, chronic kidney disease, gallstone disease, colorectal adenomatous polyp, and polycystic ovarian syndrome. NAFLD seems to be related to host metabolic factors rather than viral factors and does not seem to affect severity of the liver disease in patients with chronic hepatitis B. On the other hand, hepatic steatosis may be related to both host metabolic and viral factors in patients with chronic hepatitis C and seems to adversely impact on the severity of liver disease and possibly response to antiviral therapy.

Cyclosporine rescue therapy in autoimmune liver cirrhosis: a case report.

Autoimmune hepatitis is an inflammatory condition of the liver that can lead to significant morbidity and mortality. Corticosteroids with or without azathioprine have been shown to improve outcome and are the current standard of care in autoimmune hepatitis patients. However, long-term use of corticosteroids and use of azathioprine could be associated with significant adverse effects that prevent their continued use at optimal dosages or may even require complete cessation. We present a patient with autoimmune liver cirrhosis who was intolerant of corticosteroid and azathioprine, who was successfully treated with cyclosporine. To our knowledge, cyclosporine use has not been reported previously in autoimmune cirrhosis, although it has been used in autoimmune hepatitis patients with reported success and good tolerability. We conclude that cyclosporine seems to be an effective alternative to azathioprine as a steroid-sparing agent in both non-cirrhotic and cirrhotic autoimmune hepatitis.