Alanine aminotransferase predicts incident steatotic liver disease of metabolic etiology: Long life to the old biomarker!

Alanine aminotransferase(ALT)serum levels increase because of hepatocellular damage.Metabolic dysfunction-associated fatty liver disease(MAFLD),which identifies steatotic liver disease(SLD)associated with≥2 metabolic abnormalities,has prominent sexual differences.The Metabolic Syndrome defines a cluster comprising abdominal obesity,altered glucose metabolism,dyslipidemia,and hypertension.Male sex,body mass index,glucose,lipids,ferritin,hypertension,and age independently predict ALT levels among blood donors.Over the last few decades,the reference range of ALT levels has been animatedly debated owing to attempts to update sex-specific reference ranges.With this backset,Chen et al have recently published a study which has two main findings.First,>80%of indi-viduals with MAFLD had normal ALT levels.Second,there was a linear increa-sing trend in the association between cumulative excess high-normal ALT levels and the rate of incident MAFLD.This study has biologically credible findings.However,it inaccurately considered sex differences in the MAFLD arena.Therefore,future studies on SLD owing to metabolic dysfunction should adopt locally determined and prospectively validated reference ranges of ALT and carefully consider sex differences in liver enzymes and MAFLD pathobiology.

Elevated alanine aminotransferase activity is not associated with dyslipidemias,but related to insulin resistance and higher disease grades in non-diabetic non-alcoholic fatty liver disease

Objective:To explore demographic and metabolic factors associated with increased alanine aminotransferase(ALT)activity in non-diabetic non-alcoholic fatty liver disease(NAFLD)patients.Methods:Overall 372 patients who consecutively attended to Gastroenterology Clinic of Baqiyatallah University of Medical Sciences,Tehran,Iran awere diagnosed as NAFLD entered into analysis.Exclusion criteria were having diabetes mellitus and fasting blood glucose over126 mg/dL,active hepatitis B virus infection,having hepatitis C virus positive serology,and to be under corticosteroid therapy.ALT levels were considered pathologically high when it was over30 IU/L for men and over 19 IU/L for women.Results:Bivariate analyses using t test and chisquare test showed that patients with pathologically augmented ALT levels had significantly higher NAFLD grades in their ultrasonographic evaluations(P=0.003).Moreover,these patients represented significantly higher homeostatic model assessment levels(P=0.003),levels of serum insulin(P=0.002),fasting blood glucose(P<0.001),and uric acid(P=0.02).The prevalence of insulin resistance was also higher in patients with increased serum ALT concentrations.Multifactorial logistic regression models showed that ultrasonographic grading of NAFLD(P=0.027)and insulin resistance(P=0.013)were the only variables significantly associated with abnormal ALT levels.Conclusions:This study shows that the associations of increased ALT serum levels in NAFLD patients are different from what are supposed before.By excluding diabetic patients from our population,we find that increased ALT levels are not associated with dyslipidemias but are independently associated with insulin resistance and NAFLD grading on ultrasonographic evaluations.Further studies are needed to confirm our results.

Metabolic dysfunction-associated steatotic liver disease:The question of long-term high-normal alanine aminotransferase as a screening test

The growing prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)is being driven by the obesity epidemic.The quest for solutions continues particularly with regard to early detection.This editorial comments on the utility of long-term high-normal alanine aminotransferase(ALT)in screening for MASLD.Chen et al found that new onset MASLD can be detected by repetitively high normal ALT.Implicit in this concept is the question of what should be the accepted upper limit of normal(ULN)for ALT.It was previously set at 40 IU/L based on studies that included people with subclinical liver disease but the new consensus is 30/19 U/L in healthy males/females.Thus,when Chen et al defines the ULN as 40 U/L,others may view it as excessively high.It is important to recognize the variables affecting ULN e.g.instrumentation,diurnal variations,exercise and ageing.These variables matter when the distinctions are subtle e.g.normal vs high-normal.In this regard,the utility of long-term high normal ALT as a disease marker could be enhanced by combining it with other biomarkers,imaging and MASLD genetics to create machine learning classifiers.All in all,Chen et al’s work on long-term high normal ALT as a marker of new-onset MASLD deserves merit.

Risk Factors, Clinical Features, Baseline Alanine Aminotransferase and CD4+ Count of Children with HIV Co-Infection with Hepatitis B and C at a Tertiary Hospital in Southwest Nigeria

Background: Human immunodeficiency virus and hepatitis B and C viruses are endemic in sub- Saharan African countries including Nigeria. Researchers have studied the burden of co-infection of HIV with hepatitis B and hepatitis C but the risk factors and clinical presentation have not been much addressed especially in children. Methodology: This was a prospective cross sectional study that determined the prevalence, risk factors, clinical features, baseline CD4+ count, CD4+ percentage, and alanine aminotransferase (ALT) of newly diagnosed, HAART na?ve HIV co-infection among children who were managed at a Tertiary Hospital in Ilorin, Nigeria. Result: Of the 60 HIV- infected children recruited, 11.7% had HIV co-infection with HBV or HCV. Children with co-infec- tions (mean age 8.43 ± 2.37 years) were significantly older than their HIV mono-infected counterparts (mean age 5.25 ± 3.96 years) (p = 0.011). There was no significant difference between HIV monoinfection and HIV co-infection with respect to gender (p = 0.758), ethnicity (p = 0.707), religion of parents (p = 0.436), family type (p = 0.184), social class (p = 0.535), previous transfusion (p = 0.053), scarification (p = 0.612), female genital mutilation (p = 0.778), and sharing of clippers (p = 0.806). The mean BMI, immunological staging (p = 0.535), baseline ALT (p = 0.940), and mean baseline CD4+ count (p = 0.928) were comparable. However, the body mass index of HIV co-infec- ted children decreased with age up till age 10 years. Conclusion: There were no risk factors, nor clinical features predictive of co-infection identified in this study. Co-infection did not negatively impact baseline, CD4+ count and ALT.

Effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease:Clinical implications

In this editorial,we comment on the article by Chen et al recently published in 2024.We focus the debate on whether reducing the upper limit of normal of alanine aminotransferase(ALT)would effectively identify cases of fibrosis in metabolic-dysfunction associated fatty liver disease(MAFLD).This is important given the increasing prevalence of MAFLD and obesity globally.Currently,a suitable screening test to identify patients in the general population does not exist and most patients are screened after the finding of an abnormal ALT.The authors of this paper challenge the idea of what a normal ALT is and whether that threshold should be lowered,particularly as their study found that 83.12%of their study population with a diagnosis of MAFLD had a normal ALT.The main advantages of screening would be to identify patients and provide intervention early,the mainstay of this being changing modifiable risk factors and monitoring for liver fibrosis.However,there is not enough suitable therapeutic options available as of yet although this is likely to change in the coming years with more targets for therapy being discovered.Semaglutide is one example of this which has demonstrated benefit with an acceptable side effect profile for those patients with MAFLD and obesity,although studies have not yet shown a significant improvement in fibrosis regression.It would also require a huge amount of resource if a reduced ALT level alone was used as criteria;it is more likely that current scoring systems such as fibrosis-4 may be amended to represent this additional risk.Currently,there is not a good argument to recommend wide-spread screening with a reduced ALT level as this is unlikely to be cost-effective.This is compounded by the fact that there is a significant heterogeneity in what is considered a normal ALT between laboratories.Although studies previously have suggested a more pragmatic approach in screening those over the age of 60,this is likely to change with the increasing incidence of obesity within the younger age groups.The main message from this study is that those who have hypercholesterolemia and high body metabolic index should have these risk factors modified to maintain a lower level of ALT to reduce the risk of progression to fibrosis and cirrhosis.

Predictive value of serum alanine aminotransferase for fatty liver associated with metabolic dysfunction

In this editorial,we offer commentary on the article published by Chen et al in a recent issue of the World Journal of Gastroenterology(2024;30:1346-1357).The study highlights a noteworthy association between persistently elevated,yet highnormal levels of alanine transaminase(ALT)and an escalated cumulative risk of developing metabolic dysfunction-associated fatty liver disease(MAFLD).MAFLD has emerged as a globally prevalent chronic liver condition,whose incidence is steadily rising in parallel with improvements in living standards.Left unchecked,MAFLD can progress from hepatic steatosis to liver fibrosis,cirrhosis,and even hepatocellular carcinoma,underscoring the importance of early screening and diagnosis.ALT is widely recognized as a reliable biomarker for assessing the extent of hepatocellular damage.While ALT levels demonstrate a significant correlation with the severity of fatty liver disease,they lack specificity.The article by Chen et al contributes to our understanding of the development of MAFLD by investigating the long-term implications of high-normal ALT levels.Their findings suggest that sustained elevation within the normal range is linked to an increased likelihood of developing MAFLD,emphasizing the need for closer monitoring and potential intervention in such cases.

Healthy ranges of serum alanine aminotransferase levels in Iranian blood donors

AIM: The healthy ranges for serum alanine aminotransferase(ALT) levels are less well studied. The aim of this study was to define the upper limit of normal (ULN) for serum ALT levels, and to assess factors associated with serum ALT activity in apparently healthy blood donors. METHODS: A total of 1 939 blood donors were included.ALT measurements were performed for all cases using the same laboratory method. Healthy ranges for ALT levels werecomputed from the population at the lowest risk for liver disease. Univariate and multivariate analyses were performed to evaluate associations between clinical factors and ALT levels.RESULTS: Serum ALT activity was independently associated with body mass index (BMI) and male gender, but not associated with age. Association of ALT with BMI was more prominent in males than in females. Upper limit of normal for non-overweight women (BMI of less than 25) was 34 U/L,and for non-overweight men was 40 U/L.CONCLUSION: Serum ALT is strongly associated with sex and BMI. The normal range of ALT should be defined for male and female separately.

Cumulative effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease in China

BACKGROUND Within the normal range,elevated alanine aminotransferase(ALT)levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease(MAFLD).AIM To investigate the associations between repeated high-normal ALT measurements and the risk of new-onset MAFLD prospectively.METHODS A cohort of 3553 participants followed for four consecutive health examinations over 4 years was selected.The incidence rate,cumulative times,and equally and unequally weighted cumulative effects of excess high-normal ALT levels(ehALT)were measured.Cox proportional hazards regression was used to analyse the association between the cumulative effects of ehALT and the risk of new-onset MAFLD.RESULTS A total of 83.13%of participants with MAFLD had normal ALT levels.The incidence rate of MAFLD showed a linear increasing trend in the cumulative ehALT group.Compared with those in the low-normal ALT group,the multivariate adjusted hazard ratios of the equally and unequally weighted cumulative effects of ehALT were 1.651[95%confidence interval(CI):1.199-2.273]and 1.535(95%CI:1.119-2.106)in the third quartile and 1.616(95%CI:1.162-2.246)and 1.580(95%CI:1.155-2.162)in the fourth quartile,respectively.CONCLUSION Most participants with MAFLD had normal ALT levels.Long-term high-normal ALT levels were associated with a cumulative increased risk of new-onset MAFLD.

Alanine aminotransferase as a risk marker for new-onset metabolic dysfunction-associated fatty liver disease

In this editorial,we comment on the article by Chen et al.Metabolic dysfunction-associated fatty liver disease(MAFLD)is a global public health burden whose incidence has risen concurrently with overweight and obesity.Given its detri-mental health impact,early identification of at-risk individuals is crucial.MAFLD diagnosis is based on evidence of hepatic steatosis indicated by liver biopsy,imaging,or blood biomarkers,and one of the following conditions:Overweight/obesity,type 2 diabetes mellitus,or metabolic dysregulation.However,in large-scale epidemiological studies,liver biopsies are not feasible.The application of techniques such as ultrasonography,computed tomography,magnetic resonance imaging,and magnetic resonance spectroscopy is restricted by their limited sensitivity,low effectiveness,high costs,and need for specialized software.Blood biomarkers offer several advantages,particularly in large-scale epidemiological studies or clinical scenarios where traditional imaging techniques are impractical.Analysis of cumulative effects of excess high-normal blood alanine aminotrans-ferase(ALT)levels of blood ALT levels could facilitate identification of at-risk patients who might not be detected through conventional imaging methods.Accordingly,investigating the utility of blood biomarkers in MAFLD should enhance early detection and monitoring,enabling timely inter-vention and management and improving patient outcomes.

IL-28B polymorphisms and treatment response in hepatitis C virus patients with persistently normal alanine aminotransferase

AIM:To examine the association between the interleukin 28B(IL-28B)genotype and treatment response in hepatitis C virus(HCV)-infected patients with persistently normal alanine aminotransferase(PNALT).METHODS:We compared the treatment response of HCV-infected patients with PNALT to that of patients with non-PNALT.Between February 2010 and April2013,278 patients infected with HCV were enrolled in this study.All of the patients were treated with peginterferon-alpha 2a or 2b plus ribavirin.In addition,180μg of peginterferon alpha-2a or 1.5μg/kg peginterferon alpha-2b per week plus weight-based ribavirin(600-1000 mg/d)were typically administered for 24 wk to HCV genotype 2-infected patients or for 48-72 wk to HCV genotype 1-infected patients.In all of the patients,the IL-28B rs8099917 genotype was determined using a TaqMan single-nucleotide polymorphism assay.HCV RNA was measured using the COBAS TaqMan HCV test.RESULTS:Female patients were dominant in the PNALT group(P【0.0001).Among 72 HCV genotype 1-infected patients with PNALT,the early virologic response(EVR)rates(P【0.01)and the sustained virologic response(SVR)rates(P【0.01)were higher in patients with the IL-28B TT genotype than in those with the IL-28B TG/GG genotype.In HCV genotype 1-infected patients with PNALT,multivariate logistic-regression analysis showed that SVR was independently predicted by the IL-28B rs8099917 TT type(P【0.05)and having an EVR(P【0.01).The IL-28B rs8099917 TT genotype strongly correlated with treatment response in HCV genotype 1-infected Asian patients with PNALT.CONCLUSION:The IL-28B genotype may be useful for selecting HCV genotype 1-infected patients with PNALT who should receive interferon-based treatment.

Disease progression in chronic hepatitis C patients with normal alanine aminotransferase levels

AIM:To investigate whether the disease progression of chronic hepatitis C patients with normal alanine aminotransferase(ALT) levels differs by ALT levels.METHODS:A total of 232 chronic hepatitis C patients with normal ALT(< 40 IU/L) were analyzed.The patients were divided into "high-normal" and "low-normal" ALT groups after determining the best predictive cutoff level associated with disease progression for each gender.The incidence of disease progression,as defined by the occurrence of an increase of ≥ 2 points in the Child-Pugh score,spontaneous bacterial peritonitis,bleeding gastric or esophageal varices,hepatic encephalopathy,the development of hepatocellular carcinoma,or death related to liver disease,were compared between the two groups.RESULTS:Baseline serum ALT levels were associatedwith disease progression for both genders.The best predictive cutoff baseline serum ALT level for disease progression was 26 IU/L in males and 23 IU/L in females.The mean annual disease progression rate was 1.2% and 3.9% for male patients with baseline ALT levels ≤ 25 IU/L(low-normal) and > 26 IU/L(highnormal),respectively(P = 0.043),and it was 1.4% and 4.8% for female patients with baseline ALT levels ≤ 22 IU/L(low-normal) and > 23 IU/L(high-normal),respectively(P = 0.023).ALT levels fluctuated during the follow-up period.During the follow-up,more patients with "high-normal" ALT levels at baseline experienced ALT elevation(> 41 IU/L) than did patients with "lownormal" ALT levels at baseline(47.7% vs 27.9%,P = 0.002).The 5 year cumulative incidence of disease progression was significantly lower in patients with persistently "low-normal" ALT levels than "high-normal" ALT levels or those who exhibited an ALT elevation > 41 U/L during the follow-up period(0%,8.3% and 34.3%,P < 0.001).CONCLUSION:A "high normal" ALT level in chronic hepatitis C patients was associated with disease progression,suggesting that the currently accepted normal threshold of serum ALT should be lowered.

Alanine aminotransferase normalization at week 8 predicts viral response during hepatitis C treatment

AIM:To investigate alanine aminotransferase(ALT)and sustained virological response(SVR)in chronic hepatitis C(CHC)during peginterferon-ribavirin treatment.METHODS:One hundred and fifty-one genotype 1CHC patients underwent treatment for 48 wk with peginterferon and ribavirin,and were retrospectively divided into two groups as having a rapid virological response(RVR)(Group 1,n=52)and not having an RVR(Group 2,n=99).We also subdivided each group into two according to the initial ALT level being high(Group1h and Group 2h)or normal(Group 1n and Group 2n).HCV RNA and ALT levels were measured at baseline;at 4,12,24 and 48 wk during the treatment period;and at 24 wk follow-up.ALT levels were also obtained at 8 wk.According to the results of ALT,patients were enrolled in either the follow-up abnormal or follow-up normalized ALT groups at each interval.Patients with high and normal ALT levels were compared for each interval in terms of SVR.RESULTS:The SVR rates were 83%vs 40%(P=0.000),82%vs 84%(P=0.830),and 37%vs 44%(P=0.466)when comparing Group 1 with 2,1h with1n,and 2h with 2n,respectively.In Group 2h,the SVR rates were 34%vs 40%(P=0.701),11%vs 52%(P=0.004),12%vs 50%(P=0.007),7%vs 50%(P=0.003),6%vs 53%(P=0.001),and 0%vs 64%(P=0.000)when comparing patients with high and normalized ALT levels at week 4,8,12,24,48 and 72,respectively.The multiple logistic regression analysis revealed that RVR(OR=7.05;95%CI:3.1-16.05,P=0.000),complete early virological response(cEVR)(OR=17.55;95%CI:6.32-48.76,P=0.000),normalization of ALT at8 wk(OR=3.04;95%CI:1.31-7.06,P=0.008),and at 12 wk(OR=4.21;95%CI:1.65-10.76,P=0.002)were identified as independent significant predictive factors for SVR.CONCLUSION:Normalization of ALT at 8 wk may predict viral response during peginterferon-ribavirin treatment in genotype-1 CHC patients especially without RVR.

Lowering the threshold of alanine aminotransferase for enhanced identification of significant hepatic injury in chronic hepatitis B patients

BACKGROUND The clinical and histological features of chronic hepatitis B(CHB)patients who fall into the"grey zone(GZ)"and do not fit into conventional natural phases are unclear.AIM To explore the impact of varying the threshold of alanine aminotransferase(ALT)levels in identifying significant liver injury among GZ patients.METHODS This retrospective analysis involved a cohort of 1617 adult patients diagnosed with CHB who underwent liver biopsy.The clinical phases of CHB patients were determined based on the European Association for the Study of the Liver 2017 Clinical Practice Guidelines.GZ CHB patients were classified into four groups:GZ-A(HBeAg positive,normal ALT levels,and HBV DNA≤10^(7) IU/mL),GZ-B(HBeAg positive,elevated ALT levels,and HBV DNA<10^(4) or>10^(7) IU/mL),GZC(HBeAg negative,normal ALT levels,and HBV DNA≥2000 IU/mL),and GZ-D(HBeAg negative,elevated ALT levels,and HBV DNA≤2000 IU/mL).Significant hepatic injury(SHI)was defined as the presence of notable liver inflammation(≥G2)and/or significant fibrosis(≥S2).RESULTS The results showed that 50.22%of patients were classified as GZ,and 63.7%of GZ patients developed SHI.The study also found that lowering the ALT treatment thresholds to the American Association for the Study of Liver Diseases 2018 treatment criteria(35 U/L for men and 25 U/L for women)can more accurately identify patients with significant liver damage in the GZ phases.In total,the proportion of patients with ALT≤40 U/L who required antiviral therapy was 64.86%[(221+294)/794].When we lowered the ALT treatment threshold to the new criteria(30 U/L for men and 19 U/L for women),the same outcome was revealed,and the proportion of patients with ALT≤40 U/L who required antiviral therapy was 75.44%[(401+198)/794].Additionally,the proportion of SHI was 49.1%in patients under 30 years old and increased to 55.3%in patients over 30 years old(P=0.136).CONCLUSION These findings suggest the importance of redefining the natural phases of CHB and using new ALT treatment thresholds for better diagnosis and management of CHB patients in the GZ phases.

Declining diagnostic accuracy of non-invasive fibrosis tests is associated with elevated alanine aminotransferase in chronic hepatitis B

AIM To explore the effect of alanine aminotransferase(ALT) on the performance of non-invasive fibrosis tests in chronic hepatitis B(CHB) patients. METHODS A total of 599 treatment-naive and biopsy-proven CHB patients were included in the study. The cohort was divided into the following three groups: Normal ALT(ALT ≤ 40), slightly elevated ALT(40 < ALT ≤ 80) and elevated ALT(ALT > 80). The diagnostic performance of five common non-invasive fibrosis tests for liver fibrosis(stages S2-4), including the aspartate aminotransferase(AST)-to-platelet(PLT) ratio index(APRI), fibrosis index based on 4 factors(FIB-4), King's score, Forns index and gamma-glutamyl transpeptidase(GGT)-to-PLT ratio(GPR), were evaluated for each group. RESULTS Higher ALT levels were associated with higher non-invasive fibrosis test scores. Patients with the same fibrosis stage but higher ALT levels showed higher noninvasive test scores. The areas under the receiver operating characteristics curves(AUROCs) of the noninvasive tests for prediction of ≥ S2 were higher for patients with ALT ≤ 40 U/L(range 0.705-0.755) and 40 < ALT ≤ 80 U/L(range 0.726-0.79) than for patients with ALT > 80 U/L(range 0.604-0.701). The AUROCs for predicting ≥ S3 and S4 were higher in patients with ALT ≤ 40 U/L(range 0.736-0.814 for ≥ S3, 0.79-0.833 for S4) than in patients with 40 < ALT ≤ 80 U/L(range 0.732-0.754 for ≥ S3, range 0.626-0.723 for S4) and ALT > 80 U/L(range 0.7-0.784 for ≥ S3, range 0.662-0.719 for S4). The diagnostic accuracy of the non-invasive tests decreased in a stepwise manner with the increase in ALT.CONCLUSION ALT has a significant effect on the diagnostic performance of non-invasive fibrosis tests. The ALT level should be considered before performing these noninvasive tests.

Lower alanine aminotransferase levels are associated with increased all-cause and cardiovascular mortality in nonalcoholic fatty liver patients

BACKGROUND Serum alanine aminotransferase(ALT) levels are often considered a marker to evaluate liver disease and its severity.AIM To investigate the association between ALT levels and all-cause and cause-specific mortality in patients with nonalcoholic fatty liver disease(NAFLD).METHODS The Third National Health and Nutrition Examination Survey(NHANES-Ⅲ) from 1988 to 1994 and NHANES-Ⅲ-related mortality data from 2019 onward were used to obtain the necessary data for the study. NAFLD was defined as hepatic steatosis, as diagnosed by ultrasound, with no other liver diseases. ALT levels were categorized into four groups according to the different recommended upper limits of normal(ULN) in men and women: < 0.5 ULN, 0.5-1 ULN, 1-2 ULN, and ≥ 2 ULN. The hazard ratios for all-cause mortality and cause-specific mortality were analyzed using the Cox proportional hazard model.RESULTS Multivariate logistic regression analysis demonstrated that the odds ratio of NAFLD correlated positively with increased serum ALT levels. In patients with NAFLD, all-cause mortality and cardiovascular mortality were the highest when ALT was < 0.5 ULN, yet cancer-related mortality was the highest when ALT was ≥ 2 ULN. The same results could be found in both men and women. Univariate analysis showed that severe NAFLD with normal ALT levels had the highest allcause and cause-specific mortality, but the difference was not statistically significant after adjustment for age and multivariate factors.CONCLUSION The risk of NAFLD was positively correlated with ALT level, but all-cause and cardiovascular mortality were the highest when ALT was < 0.5 ULN. Regardless of the severity of NAFLD, normal or lower ALT levels were associated with higher mortality than elevated ALT levels. Clinicians should be aware that high ALT levels indicate liver injury, but low ALT levels are associated with a higher risk of death.

Diagnostic value of FIB-4, aspartate aminotransferaseto-platelet ratio index and liver stiffness measurement in hepatitis B virus-infected patients with persistently normal alanine aminotransferase

AIM To assess the diagnostic value of FIB-4, aspartate aminotransferase-to-platelet ratio index(APRI), and liver stiffness measurement(LSM) in patients with hepatitis B virus infection who have persistently normal alanine transaminase(PNALT).METHODS We enrolled 245 patients with chronic hepatitis B: 95 in PNALT group, 86 in intermittently elevated alanine transaminase(PIALT1) group [alanine transaminase(ALT) within 1-2 × upper limit of normal value(ULN)], and 64 in PIALT2 group(ALT > 2 × ULN). All the patients received a percutaneous liver biopsy guided by ultrasonography. LSM, biochemical tests, and complete blood cell counts were performed.RESULTS The pathological examination revealed moderate inflammatory necrosis ratios of 16.81%(16/95), 32.56%(28/86), and 45.31%(28/64), and moderate liverfibrosis of 24.2%(23/95), 33.72%(29/86), and 43.75%(28/64) in the PNALT, PIALT1, and PIALT2 groups, respectively. The degrees of inflammation and liver fibrosis were significantly higher in the PIALT groups than in the PNALT group(P < 0.05). No significant difference was found in the areas under the curve(AUCs) between APRI and FIB-4 in the PNALT group; however, significant differences were found between APRI and LSM, and between FIB-4 and LSM in the PNALT group(P < 0.05 for both). In the PIALT1 and PIALT2 groups, no significant difference(P > 0.05) was found in AUCs for all comparisons(P > 0.05 for all). In the overall patients, a significant difference in the AUCs was found only between LSM and APRI(P < 0.05).CONCLUSION APRI and FIB-4 are not the ideal noninvasive hepatic fibrosis markers for PNALT patients. LSM is superior to APRI and FIB-4 in PNALT patients because of the influence of liver inflammation and necrosis.

Non-ALT biomarkers for markedly abnormal liver histology among Chinese persistently normal alanine aminotransferase-chronic hepatitis B patients

AIM To determine incidence and clinical biomarkers of marked necroinflammation and fibrosis characteristics among chronic hepatitis B (CHB) patients with persistently normal alanine aminotransferase (PNALT). METHODS Liver biopsy was performed on 115 CHB patients with PNALT. Necroinflammation and fibrosis were graded by the Knodell histologic activity index and the Ishak fibrosis score, respectively. Correlations between the available clinical parameters and necroinflammation and fibrosis were analysed. RESULTS Marked necroinflammation (Knodell activity index >= 7) and fibrosis (Ishak fibrosis score >= 3) were found in 36.5% and 15.5% of CHB patients with PNALT, respectively. Following a univariate logistic regression analysis, multiple logistic regression analysis indicated that aspartate transaminase (AST) (AUROC = 0.852, cut-off value = 22.5 U/L) serves as an independent predictor of notable liver inflammation, while platelet (PLT) count (AUROC = 0.905, cut-off value = 171.5 x 10(9)/ml) and gamma-glutamyl transpeptidase (GGT) (AUROC = 0.909, cut-off value = 21.5 U/L) level serve as independent predictors of notable liver fibrosis. CONCLUSION A considerable proportion of marked histological abnormalities existed in our cohort, who will benefit from optimal therapeutic strategies administered according to predictive indication by AST, PLT and GGT levels.

Drug-induced liver injury in hospitalized patients with notably elevated alanine aminotransferase

AIM： To identify the proportion, causes and the nature of drug-induced liver injury （DILI） in patients with no- tably elevated alanine aminotransferase （ALT）. METHODS： All the inpatients with ALT levels above 10 times upper limit of normal range （ULN） were ret- rospectively identified from a computerized clinical laboratory database at our hospital covering a 12-mo period. Relevant clinical information was obtained from medical records. Alternative causes of ALT eleva- tions were examined for each patient, including bili- ary abnormality, viral hepatitis, hemodynamic injury, malignancy, DILI or undetermined and other causes. All suspected DILI cases were causality assessed usingthe Council for International Organizations of Medical Sciences scale, and only the cases classified as highly probable, probable, or possible were diagnosed as DILI. Comments related to the diagnosis of DILI in the medical record and in the discharge letter for each case were also examined to evaluate DILI detection by the treating doctors. RESULTS： A total of 129 cases with ALT 〉 i0 ULN were identified. Hemodynamic injury （n = 46, 35.7%）, DILl （n = 25, 19.4%） and malignancy （n = 21, 16.3%） were the top three causes of liver injury. Peak ALT val- ues were lower in DILI patients than in patients with hemodynamic injury （14.5 5.6 ULN vs 32.5 ：I： 30.7 ULN, P = 0.001）. Among DILI patients, one （4%） case was classified as definite, 19 （76%） cases were clas- sified as probable and 5 （20%） as possible according to the ClOMS scale. A hepatocellular pattern was ob- served in 23 （92%） cases and mixed in 2 （8%）. The extent of severity of liver injury was mild in 21 （84%） patients and moderate in 4 （16%）. Before discharge, 10 （40%） patients were recovered and the other 15 （60%） were improved. The improved patients tended to have a higher peak ALT （808 ＋ 348 U/L vs 623 ＋ 118 U/L, P = 0.016） and shorter treatment duration before discharge （8 ＋ 6 d vs 28 ~ 12 d, P = 0.008） compared with the recovered patients. Twenty-two drugs and 6 herbs were found associated with DILl. Antibacterials were the most common agents causing DILI in 8 （32%） cases, followed by glucocorticoids in 6 （24%） cases. Twenty-four （96%） cases received treatment of DILl with at least one adjunctive drug. Agents for treatment of DILI included anti-inflammatory drugs （e.g., glycyr- rhizinate）, antioxidants （e.g., glutathione, ademetionine 1,4-butanedisulfonate and tiopronin）, polyene phospha- tidyl choline and herbal extracts （e.g., protoporphyrin disodium and silymarin）. Diagnosis of DILl was not mentioned in the discharge letter in 60% of the cases. Relative to prevalent cases and cases from wards of internal medicine, incident cases and cases from surgi- cal wards had a higher risk of missed diagnosis in dis- charge letter [odds ratio （OR） 32.7, 95%CI （2.8-374.1）,CONCLUSION： DILI is mostly caused by use of anti- bacterials and glucocorticoids, and constitutes about one fifth of hospitalized patients with ALT 〉 10 ULN. DILI is underdiagnosed frequently.

A better parameter in predicting insulin resistance:Obesity plus elevated alanine aminotransferase

AIM:To investigate the association of obesity and elevated alanine aminotransferase with insulin resistance and compare these factors with metabolic syndrome. METHODS:We enrolled a total of 1308 male workers aged from 22 to 63 years.Data was extracted from the workers'periodic health check-ups in hospitals.All cases were from the community of northern Taiwan. This was a cross-sectional observational study from July to September in 2004.We grouped all cases into four groups,based on the quartile of homeostasis model assessment.The top fourth quartile group was defined as the group with insulin resistance.We performed multivariate logistic regression analysis for the odds ratio of the risk factors for insulin resistance. RESULTS:Compared with metabolic syndrome,the coexistence of both factors had a 4.3-fold(95%CI: 2.7-6.8)increased risk,which was more than metabolic syndrome with a 3.6-fold(95%CI:2.6-5.0)increased risk.The two factors had a synergistic effect.The synergistic index of obesity and elevated alanine aminotransferase(ALT)was 2.1(95%CI:1.01-4.3).CONCLUSION:Obesity and elevated ALT are associatedwith insulin resistance.The effects are synergistic. Coexistence of them is better than metabolic syndrome in predicting insulin resistance.

Postoperative day one serum alanine aminotransferase does not predict patient morbidity and mortality after elective liver resection in non-cirrhotic patients

ABSTRACT： Serum aminotransferases have been used as surrogate markers for liver ischemia-reperfusion injury that follows liver surgery. Some studies have suggested that rises in serum alanine aminotransferase （ALT） correlate with patient outcome after liver resection. We assessed whether postoperative day 1 （POD 1） ALT could be used to predict patient morbidity and mortality following liver resection. We reviewed our prospectively held database and included consecutive adult patients undergoing elective liver resection in our institution between January 2013 and December 2014. Primary outcome assessed was correlation of POD 1 ALT with patient＇s morbidity and mortality. We also assessed whether concurrent radiofrequency ablation, neoadjuvant chemotherapy and use of the Pringle maneuver significantly affected the level of POD 1 ALT. A total of 110 liver resections were included in the study. The overall in-hospital patient morbidity and mortality were 31.8% and 0.9%, respectively. The median level of POD 1 ALT was 275 IU/L. No correlation was found between POD 1 serum ALT levels and patient morbidity after elective liver resection, whilst correlation with mortality was not possible because ofthe low number of mortalities. Patients undergoing concurrent radiofrequency ablation were noted to have an increased level of POD 1 serum ALT but not those given neoadjuvant chemotherapy and those in whom the Pringle maneuver was used. Our study demonstrates POD 1 serum ALT does not correlate with patient morbidity after elective liver resection.