Prevalence and risk factors for impaired renal function among Asian patients with nonalcoholic fatty liver disease

Background:Nonalcoholic fatty liver disease(NAFLD)is associated with impaired renal function,and both diseases often occur alongside other metabolic disorders.However,the prevalence and risk factors for impaired renal function in patients with NAFLD remain unclear.The objective of this study was to identify the prevalence and risk factors for renal impairment in NAFLD patients.Methods:All adults aged 18-70 years with ultrasound-diagnosed NAFLD and transient elastography examination from eight Asian centers were enrolled in this prospective study.Liver fibrosis and cirrhosis were assessed by FibroScan-aspartate aminotransferase(FAST),Agile 3+and Agile 4 scores.Impaired renal function and chronic kidney disease(CKD)were defined by an estimated glomerular filtration rate(eGFR)with value of<90 mL/min/1.73 m^(2) and<60 mL/min/1.73 m^(2),respectively,as estimated by the CKD-Epidemiology Collaboration(CKD-EPI)equation.Results:Among 529 included NAFLD patients,the prevalence rates of impaired renal function and CKD were 37.4%and 4.9%,respectively.In multivariate analysis,a moderate-high risk of advanced liver fibrosis and cirrhosis according to Agile 3+and Agile 4 scores were independent risk factors for CKD(P<0.05).Furthermore,increased fasting plasma glucose(FPG)and blood pressure were significantly associated with impaired renal function after controlling for the other components of metabolic syndrome(P<0.05).Compared with patients with normoglycemia,those with prediabetes[FPG≥5.6 mmol/L or hemoglobin A1c(HbA1c)≥5.7%]were more likely to have impaired renal function(P<0.05).Conclusions:Agile 3+and Agile 4 are reliable for identifying NAFLD patients with high risk of CKD.Early glycemic control in the prediabetic stage might have a potential renoprotective role in these patients.

Transient elastography: Kill two birds with one stone?

Assessment of liver fibrosis and steatosis is crucial in chronic liver diseases in order to determine the prognosis, the need of treatment, as well as monitor disease progression and response to treatment. Liver biopsy is limited by its invasiveness and patient acceptability. Transient elastography (TE, Fibroscan ) is a non-invasive tool with satisfactory accuracy and reproducibility to estimate liver fibrosis and steatosis. TE has been well validated in major liver diseases including chronic hepatitis B and C, non-alcoholic fatty liver disease, alcoholic liver disease, primary biliary cirrhosis, and primary sclerosing cholangitis. As alanine aminotransferase (ALT) is one of the major confounding factors of liver stiffness in chronic hepatitis B, an ALT-based algorithm has been developed and higher liver stiffness measurements (LSM) cutoff values for different stages of liver fibrosis should be used in patients with elevated ALT levels up to 5 times of the upper limit of normal. Otherwise falsely-high LSM results up to cirrhotic range may occur during ALT flare. TE is also useful in predicting patient prognosis such as development of hepatocellular carcinoma (HCC), portal hypertension, post-operative complications in HCC patients, and also survival. Unfortunately, failed acquisition of TE is common in obese patients. Furthermore,obese patients may have higher LSM results even in the same stage of liver fibrosis. The new XL probe, a larger probe with lower ultrasound frequency and deeper penetration, increases the success rate of TE in obese patients. The median LSM value with XL probe was found to be lower than that by the conventional M probe, hence cutoff values approximately 1.2 to 1.3 kPa lower than those of M probe should be adopted. Recent studies revealed a novel ultrasonic controlled attenuation parameter (CAP) of the machine is a useful parameter to detect even low-grade steatosis noninvasively. CAP may also be used to quantify liver steatosis by applying different cutoff values. As both LSM and CAP results are instantly available at same measurement, this makes TE a very convenient tool to assess any patients who are suspected or confirmed to suffer from chronic liver diseases.

WJG 20^(th) Anniversary Special Issues(1): Hepatocellular carcinoma Risk prediction of hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy

Chronic hepatitis B(CHB)-related hepatocellular carcinoma(HCC)is a major health problem in AsianPacific regions.Antiviral therapy reduces,but does not eliminate the risk of HCC.It would be a heavy financial burden in most low and middle economic countries if all CHB patients received antiviral therapy and HCC surveillance.Thus,there is a need for accurate risk prediction to assist prognostication,decisions on the need for antiviral therapy and HCC surveillance.A few wellestablished risk factors for HCC,namely advanced age,male gender,high viral load,cirrhosis etc.,are the core components of three HCC risk scores:CU-HCC,GAGHCC and REACH-B scores.These 3 scores were confirmed to be accurate in predicting HCC up to 10 years in treatment-na ve patients.Their validity and applicability have recently been demonstrated in a large cohort of entecavir treatment patients.A decrease in risk scores after antiviral therapy translates to a lower risk of HCC.These findings support the application of HCC risk scores in all CHB patients.Different levels of care and different intensities of HCC surveillance should be offered according to the risk profile of patients.Patients at risk of HCC should undergo regular HCC surveillance,even when they are receiving antiviral treatment.

Detection of focal liver lesions in cirrhotic liver using contrast-enhanced ultrasound

Patients with liver cirrhosis are at increased risk of hepatocellular carcinoma(HCC).Conventional or baseline ultrasound(BUS)is often used as the first-line tool for HCC surveillance or detection,but the accuracy of BUS in HCC detection or differentiation from other focal liver lesions(FLLs)is limited.Contrast-enhanced ultrasound(CEUS)represents a recent revolution in the field of ultrasonography and it has become increasingly important in the detection and evaluation of FLLs.In CEUS,HCC typically exhibits arterial hyper-enhancement and portal-venous washout represented by hypoenhanced lesions in the portal venous and late phases.The detection rate of HCC was significantly higher with CEUS compared with BUS.Even regenerative or some dysplastic nodules may exhibit arterial hyperenhancement as they are differentiated from HCC by its iso-enhancing pattern in portal and late phases.The contrast-enhancement patterns of other different types of benign and malignant FLLs,as well as their detection rates with CEUS,were also discussed.

Optimal surveillance program for hepatocellular carcinoma- getting ready, but not yet

Hepatocellular carcinoma(HCC) secondary to chronic viral hepatitis is a major health problem in AsianPacific regions due to the endemics of chronic hepatitis B and C virus infection. HCC surveillance has been recommended to patients who are at risk to develop HCC. Unfortunately, a significant proportion of patients still died in long run due to tumor recurrence. The key components of an optimal surveillance program include an accurate tumor biomarker and optimal surveillance interval. Serum alpha-fetoprotein(AFP), despite of being the most widely used biomarker for HCC surveillance, it was criticized as neither sensitive nor specific. Other HCC biomarkers, including lectin-reactive AFP(AFP-L3), des-gamma carboxyprothrombin, are still under investigations. Recent study showed cancerassociated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing to be accurate with both sensitivity and specificity close to 90% in detecting HCC in a case-control study. Concerning the optimal surveillance interval, we believe one size does not fit all patients. Accurate risk prediction to assist prognostication with well-validated HCC risk scores would be useful to decide the need for HCC surveillance. These key components of an optimal HCC surveillance program should be further validated at a surveillance setting.

Validation model of fibrosis-8 index score to predict significant fibrosis among patients with nonalcoholic fatty liver disease

BACKGROUND Identifying hepatic fibrosis is crucial for nonalcoholic fatty liver disease(NAFLD)management.The fibrosis-8(FIB-8)score,recently developed by incorporating four additional variables into the fibrosis-4(FIB-4)score,showed better performance in predicting significant fibrosis in NAFLD.AIM To validate the FIB-8 score in a biopsy-proven NAFLD cohort and compare the diagnostic performance of the FIB-8 and FIB-4 scores and NAFLD fibrosis score(NFS)for predicting significant fibrosis.METHODS We collected the data of biopsy-proven NAFLD patients from three Asian centers in three countries.All the patients with available variables for the FIB-4 score(age,platelet count,and aspartate and alanine aminotransferase levels)and FIB-8 score(the FIB-4 variables plus 4 additional parameters:The body mass index(BMI),albumin to globulin ratio,gamma-glutamyl transferase level,and presence of diabetes mellitus)were included.The fibrosis stage was scored using nonalcoholic steatohepatitis CRN criteria,and significant fibrosis was defined as at least fibrosis stage 2.RESULTS A total of 511 patients with biopsy-proven NAFLD and complete data were included for validation.Of these 511 patients,271(53.0%)were female,with a median age of 51(interquartile range:41,58)years.The median BMI was 29(26.3,32.6)kg/m2,and 268(52.4%)had diabetes.Among the 511 NAFLD patients,157(30.7%)had significant fibrosis(≥F2).The areas under the receiver operating characteristic curves of the FIB-8 and FIB-4 scores and NFS for predicting significant fibrosis were 0.774,0.743,and 0.680,respectively.The FIB-8 score demonstrated significantly better performance for predicting significant fibrosis than the NFS(P=0.001)and was also clinically superior to FIB-4,although statistical significance was not reached(P=0.073).The low cutoff point of the FIB-8 score for predicting significant fibrosis of 0.88 showed 92.36%sensitivity,and the high cutoff point of the FIB-8 score for predicting significant fibrosis of 1.77 showed 67.51%specificity.CONCLUSION We demonstrated that the FIB-8 score had significantly better performance for predicting significant fibrosis in NAFLD patients than the NFS,as well as clinically superior performance vs the FIB-4 score in an Asian population.A novel simple fibrosis score comprising commonly accessible basic laboratories may be beneficial to use for an initial assessment in primary care units,excluding patients with significant liver fibrosis and aiding in patient selection for further hepatologist referral.

Hepatocyte apoptosis fragment product cytokeratin-18 M30 level and non-alcoholic steatohepatitis risk diagnosis:an international registry study

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.

Epidemiology and Clinical Outcomes of Metabolic(Dysfunction)-associated Fatty Liver Disease

Metabolic(dysfunction)-associated fatty liver disease(MAFLD)is currently the most common chronic liver disease and affects at least a quarter of the global adult population.It has rapidly become one of the leading causes of hepatocellular carcinoma and cirrhosis in Western countries.In this review,we discuss the nomenclature and definition of MAFLD as well as its prevalence and incidence in different geographical regions.Although cardiovascular disease remains the leading cause of death in MAFLD patients,the proportion of patients dying from hepatic complications increases sharply as the disease progresses to advanced liver fibrosis and cirrhosis.In addition,patients with MAFLD are at increased risk of various extrahepatic cancers.Although a causal relationship between MAFLD and extrahepatic cancers has not been established,clinicians should recognize the association and consider cancer screening(e.g.,for colorectal cancer)as appropriate.

Non-invasive tests of non-alcoholic fatty liver disease

For the detection of steatosis,quantitative ultrasound imaging techniques have achieved great progress in past years.Magnetic resonance imaging proton density fat fraction is currently the most accurate test to detect hepatic steatosis.Some blood biomarkers correlate with non-alcoholic steatohepatitis,but the accuracy is modest.Regarding liver fibrosis,liver stiffness measurement by transient elastography(TE)has high accuracy and is widely used across the world.Magnetic resonance elastography is marginally better than TE but is limited by its cost and availability.Several blood biomarkers of fibrosis have been used in clinical trials and hold promise for selecting patients for treatment and monitoring treatment response.This article reviews new developments in the non-invasive assessment of non-alcoholic fatty liver disease(NAFLD).Accumulating evidence suggests that various non-invasive tests can be used to diagnose NAFLD,assess its severity,and predict the prognosis.Further studies are needed to determine the role of the tests as monitoring tools.We cannot overemphasize the importance of context in selecting appropriate tests.

Update of liver fibrosis and steatosis with transient elastography (Fibroscan)

Background:Assessment of liver fibrosis and steatosis is now almost indispensable in most of the chronic liver diseases in order to determine prognosis and need for treatment,and to monitor disease progression and response to treatment.Liver biopsy is limited by its invasiveness and patient acceptability.Transient elastography(TE;Fibroscan)is a non-invasive tool with satisfactory accuracy and reproducibility to estimate liver fibrosis.Aims&Methods:To review the existing evidence concerning the clinical applications of TE in major liver diseases,including chronic hepatitis B and-C,non-alcoholic fatty liver disease(NAFLD),alcoholic liver disease,primary biliary cirrhosis and primary sclerosing cholangitis.Results:As alanine aminotransferase(ALT)is one of the major confounding factors of liver stiffness in chronic hepatitis B,an ALT-based algorithm has been developed and higher liver stiffness measurements(LSM)cut-off values for different stages of liver fibrosis should be used in patients with elevated ALT levels up to five times the upper limit of normal.Furthermore,falsely-high LSM results up to the cirrhotic range may occur during ALT flare.TE is also useful predicting patient prognosis in the development of hepatocellular carcinoma(HCC),portal hypertension,postoperative complications in HCC patients and survival.Unfortunately,failed acquisition of TE is common in obese patients.Furthermore,obese patients may have higher LSM results,even in the same stage of liver fibrosis.To better evaluate NAFLD a new XL probe,with a larger probe with lower ultrasound frequency and deeper penetration,increases the success rate of TE in obese patients.The median LSM value with the XL probe was found to be lower than that by the conventional M probe,hence cut-off values were approximately 1.2 to 1.3 kilopascals lower than those of the M probe,suggesting its adoption.Studies reveal that a novel ultrasonic controlled attenuation parameter is potentially useful to detect and quantify hepatic steatosis non-invasively.Conclusion:TE is a non-invasive,accurate and reproducible test of liver fibrosis and possibly hepatic steatosis and has been validated in a wide spectrum of liver diseases.TE is also useful to predict patient outcomes.

Advances in the diagnosis and treatment of liver fibrosis

Liver fibrosis is the center of diagnosis and management of essentially all chronic liver diseases. While liver biopsy examination still has a role in diagnosis and drug development, it is replaced by non-invasive assessments of liver biopsy in majority of the clinical scenarios. Radiological approaches, namely transient elastography, acoustic radiation force impulse imaging, shear wave elastography, magnetic resonance elastography provide accurate diagnosis of advanced fibrosis and cirrhosis. Serum test formulae based on common laboratory parameters or more specialized parameters including those commercially available panels FibroTest?, FibroMeter? and Enhanced Liver Fibrosis are also available. Combining different modalities may further improve the accuracy. The role of all these non-invasive assessments has been further expanded from diagnostic to prognostic, e.g. risk prediction of hepatocellular carcinoma (HCC) by LSM-HCC score. Treatment of liver fibrosis can be achieved by controlling the underlying diseases, with chronic viral hepatitis as the most established disease model. Currently there are multiple clinical trials evaluating different treatment options to improve fibrosis in patients with non-alcoholic fatty liver disease. Specific anti-fibrotic treatment targets e.g. direct downregulation of hepatic stellate cell, collagen synthesis inhibitors and transforming growth factor-βantagonists have been tested in laboratory and pending further studies in clinical settings.

Overview of methodologies and statistical strategies in observational studies and meta-analyses on the risk of hepatocellular carcinoma in patients with chronic hepatitis B on entecavir or tenofovir therapy

Entecavir(ETV)and tenofovir disoproxil fumarate(TDF)are first-line antiviral therapies for patients with chronic hepatitis B(CHB)and reduce the risk of disease progression and liver-related complications,as well as improve survival by effectively suppressing viral replication.Nevertheless,since the first publication in 2019 on a lower risk of hepatocellular carcinoma(HCC)in Korean patients receiving TDF than those receiving ETV,the topic has remained a hot and unsettled debate.Multiple studies and meta-analyses have yielded conflicting results.As HCC takes time to develop,studies are mainly observational to benefit from a larger sample size and longer follow-up that provides a higher statistical power to compare the two treatments.However,TDF was available to CHB patients a few years later than ETV in most countries,thus leading to a difference in follow-up duration.Moreover,despite studying the same topic,the difference in data sources and available parameters,inclusion and exclusion criteria,and use of statistical methods complicated the interpretation and comparison of the findings and contributed to between-study heterogeneity in meta-analyses.This review describes some caveats in interpreting and comparing the results from these observational studies and meta-analyses.Future studies should explore better designed observational studies with high-quality data sources,and aggregation of patient data in metaanalysis to tackle between-study heterogeneity.