High-normal Alanine Aminotransferase Research Articles

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.

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 individuals with MAFLD had normal ALT levels. Second, there was a linear increasing 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.

High normal alanine aminotransferase is an indicator for better response to antiviral therapy in chronic hepatitis B.

Evidence shows people living with CHB even with a normal ALT (40U/L as threshold) suffer histological disease and there is still little research to evaluate the potential benefit of antiviral benefits in them. We retrospectively examined 1352 patients who underwent liver biopsy from 2017 to 2021 and then obtained their 1-year follow-up data to analyze. ALT levels were categorized into high and low, with thresholds set at >29 for males and >15 for females through Youden's Index. The high normal ALT group showed significant histological disease at baseline (56.43% vs 43.82%, p< 0.001), and better HBV DNA clearance from treatment using PSM (p=0.005). Similar results were obtained using 2016 AASLD high normals (male >30, female >19). Further multivariate logistic analysis showed that high normal ALT (both criterias) was an independent predictor of treatment (OR 1.993, 95% CI 1.115-3.560, p=0.020; OR 2.000, 95% CI 1.055-3.793, p=0.034) Both of the models had higher AUC compared with current scoring system, and there was no obvious difference between the two models (AUC:0.8840 vs 0.8835). Male >30 or female >19 and Male >29 or female>15 are suggested to be better thresholds for normal ALT. Having a high normal ALT in CHB provides a potential benefit in antiviral therapy.

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.

THU-199 - The prevelance of hepatitis C virus infection in high-risk patients with high normal alanine aminotransferase (ALT) in Israel: a bio bank analysis

THU-199 - The prevelance of hepatitis C virus infection in high-risk patients with high normal alanine aminotransferase (ALT) in Israel: a bio bank analysis

The Role of Metabolic Factors and Steatosis in Treatment-Naïve Patients with Chronic Hepatitis B and Normal Alanine Aminotransferase

IntroductionWe aimed to elucidate the impact of metabolic syndrome (MS) and nonalcoholic fatty liver disease (NAFLD) on treatment-naïve patients with chronic hepatitis B (CHB) and normal alanine aminotransferase (ALT).MethodsWe analyzed the clinical characteristics of a cross-sectional cohort of treatment-naïve patients with CHB and ALT in the upper limit of normal (ULN) from October 2018 to July 2021. ALT ≤ 0.5 ULN was stratified as low-normal ALT (LNALT) and 0.5 ULN < ALT ≤ ULN as high-normal ALT (HNALT). Transient elastography (TE) was used to evaluate liver steatosis and fibrosis.ResultsAmong 733 patients with CHB enrolled, 23.1% of them had MS, 37.2% of them had NAFLD, and 5.9% of them had significant fibrosis. The proportions of patients with MS, steatosis, and significant fibrosis in the HNALT group were higher than those in the LNALT group (31.4% vs. 14.1%, p < 0.001; 48.7% vs. 25.2%, p < 0.001; and 8.0% vs. 3.6%, p = 0.013, respectively). Multiple linear regression showed that steatosis (beta = 0.098, p = 0.001) and MS (beta = 0.092, p = 0.002) were independently related to ALT levels in the normal range. Multivariate logistic regression showed that age (OR 1.049, 95% CI 1.012–1.087, p = 0.010), aspartate aminotransferase (AST) (OR 1.059, 95% CI 1.005–1.115, p = 0.030), and severe steatosis (OR 2.559, 95% CI 1.212–5.403, p = 0.014) were independently associated with significant fibrosis. When analyzed in the subgroup of CHB with NAFLD, age (OR 1.060, 95% CI 1.006–1.117, p = 0.029) and severe steatosis (OR 2.962, 95% CI 1.126–7.792, p = 0.028) were still statistically significant.ConclusionThe accumulation of MS components exacerbated hepatic steatosis. Severe NAFLD was independently associated with significant fibrosis. This emphasizes the importance of screening for MS and NAFLD in patients with CHB and normal ALT, where a more active intervention may apply.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00629-5.

Low ALT levels are associated with poor outcomes in acute coronary syndrome patients in the intensive cardiac care unit

BackgroundFrailty is an underrecognized and important entity that bears worse prognosis. Although low serum alanine aminotransferase (ALT) can serve as a novel marker of frailty, its use was never assessed in acute coronary syndrome (ACS) patients. MethodsA retrospective analysis of hospitalized ACS patients in the intensive cardiac care unit (ICCU)between 1/5/2011 and 1/12/2020 at a single tertiary medical center. ResultsThe study included 3956 patients after excluding patients with ALT >40 IU/L, cirrhosis, and missing data, followed for a medianduration of 47 months (IQR 20-77).Patients were stratified into two groups based on their first ALT measurement within the index hospitalization: low-normal ALT group (ALT ≤10 IU/L) vs. high-normal ALT group (ALT >10 IU/L). Patients with ALT≤10 IU/L were older (mean age 71 years vs. 65 years, p<0.001), presented more frequently with non-ST elevation myocardial infarction (66.4% vs. 53.2%, p< 0.001), had higher rates of comorbiditiesat baseline, and had a lower Norton score upon admission. Hospitalization length was longer in the low-normal ALT group (p< 0.001). Although the in-hospital mortality rate was similar between the groups (0.9% vs. 0.7%, p = 0.99), long-termmortality was significantly higher in the low-normal ALT group (22.7% vs. 7.9%, p< 0.001). In a multivariate regression model ALT ≤10 IU/l was associated with increased mortality (HR 2.1, 95% CI 1.46-3). ConclusionsLower serum ALT is associated with worse outcomes in ACS patients admitted to the ICCU.

Low ALT levels are associated with poor outcomes in acute coronary syndrome patients admitted to the intensive cardiac care unit

Abstract Background Frailty is an under recognized and important entity that bears worse prognosis. Purpose Although low serum alanine aminotransferase (ALT) can serve as a novel marker of frailty, its use was never assessed in acute coronary syndrome (ACS) patients. Methods A retrospective analysis of hospitalized ACS patients in the intensive cardiac care unit (ICCU) between 1/5/2011 and 1/12/2020 at a single tertiary medical center. Results The study included 3956 patients after excluding patients with ALT &amp;gt;40 IU/L, cirrhosis and missing data, followed for a median duration of 47 months (IQR 20–77). Patients were stratified into two groups based on their first ALT measurement within the index hospitalization: low-normal ALT group (ALT ≤10 IU/L) vs. high-normal ALT group (ALT &amp;gt;10 IU/L). Patients with ALT≤10 IU/L were older (mean age 71 vs. 65, P&amp;lt;0.001), presented more frequently with non-ST elevation myocardial infarction (66.4% vs. 53.2%, P&amp;lt;0.001), had higher rates of comorbidities at baseline, and had a lower Norton score upon admission. Hospitalization length was longer in the low-normal ALT group (P&amp;lt;0.001). Although the in-hospital mortality rate was similar between the groups (0.9% vs. 0.7%, P=0.99), long-term mortality was significantly higher in the low-normal ALT group (22.7% vs. 7.9%, P&amp;lt;0.001). In a multivariate regression model ALT ≤10 IU/l was associated with increased mortality (HR 2.1, 95% CI 1.46–3). Conclusion Lower serum ALT is associated with worse outcomes in ACS patients admitted to the ICCU. Funding Acknowledgement Type of funding sources: None. 5-year survival according to baseline ALForest plot of variables associated with

High-normal alanine aminotransferase is an indicator for liver histopathology in HBeAg-negative chronic hepatitis B.

We aimed to assess liver histological changes of HBeAg-negative chronic hepatitis B (CHB) patients with normal ALT, and determined the association between significant liver injury and age, ALT, and HBV DNA levels. We retrospectively examined 327 patients who underwent liver biopsy from 2009 to 2018. Significant liver histological change is defined as liver necroinflammation ≥ G2 and/or liver fibrosis ≥ F2. The proportion of patients with significant liver necroinflammation or fibrosis in the high-normal ALT group (ALT > 20 U/L) was higher than that in the low-normal ALT group (ALT ≤ 20 U/L) (44.6% vs 26.5%, 61.0% vs 41.7%, p < 0.01); also the proportion in the group with HBV DNA ≥ 2000IU/mL was significantly higher than that in the group with HBV DNA < 2000IU/mL (58.5% vs 27.1%, 67.9% vs 46.2%, p < 0.01). There was no significant difference in hepatic histopathology between < 40 and ≥ 40years groups. Among 221 patients with normal ALT and low HBV DNA levels (< 2000IU/mL), 27.1% of them had significant liver necroinflammation and 46.2% had significant liver fibrosis. The multiple logistic regression analysis showed that ALT > 20 U/L and HBV DNA ≥ 2000IU/mL were independently associated with significant liver histopathology (p < 0.01). HBeAg-negative CHB patients with normal ALT and low HBV DNA level (< 2000IU/mL) were suggested to perform liver biopsy or noninvasive methods for histopathology assessment, then to be determined for antiviral therapy. ALT > 20 U/L and HBV DNA ≥ 2000IU/mL are good independently predictive factors for evaluating significant liver histopathology for HBeAg-negative CHB patients with normal ALT. Chinese Clinical Trial Registry (ChiCTR-IOR-14005474).

Alanine aminotransferase blood levels and rehabilitation outcome in older adults following hip fracture surgery.

Low alanine aminotransferase (ALT) blood levels are associated with frailty and poor outcome in older adults. Therefore, we studied the association between ALT blood levels before rehabilitation and rehabilitation outcome in older adults following hip fracture surgery. A total of 490 older adults (age>60 years, mean age: 82.9±6.7 years, 82.0% women) admitted to rehabilitation following hip fracture surgery were included. The rehabilitation outcome was assessed by Functional Independence Measure (FIM) scores. ALT blood levels were documented between 1 and 6 months before rehabilitation. Patients with ALT blood levels over 40 IU/l possibly consistent with liver injury were excluded. The cohort was divided into two groups: patients with ALT more than 10 IU/l and patients with ALT less than or equal to 10 IU/l. Upon rehabilitation discharge, the FIM outcome measures (motor, cognitive, gain, efficiency) were significantly higher in patients with ALT more than 10 IU/l relative to patients with ALT less than or equal to 10 IU/l (P<0.05). A logistic regression analysis adjusted for age and sex showed that patients with ALT more than 10 IU/l were more likely to have higher (second to fourth upper quartiles) total FIM scores (>50), cognitive FIM scores (>16), and FIM efficiency (>0.228) upon rehabilitation discharge (odds ratio=1.56-1.78). However, this association was no longer significant following adjustment also for admission total FIM score, cognitive impairment, cancer, and albumin serum levels. High-normal ALT blood levels before rehabilitation are associated with a better rehabilitation outcome in older adults following hip fracture surgery. It may be used when data on admission FIM score, cognitive impairment, cancer, and albumin serum levels are not available.

Liver fibrosis progression in chronic hepatitis B patients positive for hepatitis B e antigen: A prospective cohort study with paired transient elastography examination

Chronic hepatitis B patients in immune-reactive hepatitis B e antigen (HBeAg)-positive phase may have more rapid progression than those in immune-tolerant phase. We aimed to evaluate the risk of liver fibrosis progression in HBeAg-positive patients at different phases. Two hundred forty-seven HBeAg-positive patients without advanced fibrosis at baseline underwent liver stiffness measurement (LSM) by transient elastography in 2006-2008 and again in 2010-2012. Liver fibrosis progression was defined as increase in LSM by 30% or more to levels suggestive of advanced fibrosis at the second assessment. At baseline, the mean age was 38 ± 11 years, 58% were males, alanine aminotransferase (ALT) was 65 ± 52 IU/L, hepatitis B virus DNA was 4.2 ± 1.2 log IU/mL, and LSM was 6.3 ± 2.1 kPa. At an interval of 42 ± 6 months, 13 patients (5.2%) developed liver fibrosis progression, and 106 patients (42.9%) required antiviral therapy. None of the clinical parameters (e.g., gender, age, ALT, hepatitis B virus DNA, hepatitis B surface antigen level, etc.) was associated with liver fibrosis progression. Among 74 and 137 patients in immune-tolerant and immune-reactive phase, 4.1% and 6.6% had liver fibrosis progression, and 12.2% and 67.2% received antiviral therapy respectively (P = 0.45 and P < 0.001). Immune-tolerant patients with low-normal (< 0.5× upper limit of normal) or high-normal ALT (0.5-1× upper limit of normal) also had similar risk of liver fibrosis progression (5.7% vs. 2.6%; P = 0.49). Liver fibrosis progression is uncommon in HBeAg-positive patients. Patients in immune-reactive phase treated with antiviral therapy did not have increased risk of liver fibrosis progression.

Assessment of Clinical Utility of Low and High Normal Alanine Aminotransferase Values in Patients with Chronic Hepatitis B Virus Infection in Bangladesh

Background/Aims: There is a lack of consensus about the currently accepted range of normal values for serum alanine aminotransferase (ALT) levels because some investigators have claimed that the true values are significantly lower than those listed by kit manufacturers. Methods: A total of 255 chronic hepatitis-B-virus (HBV)-infected patients with traditional, normal levels of ALT (≤42 U/l) were divided into 2 groups: (1) low normal ALT (men: ≤30 U/l; women: ≤19 U/l) and (2) high normal ALT (men: 31–42 U/l; women: 20–42 U/l). The extent of hepatic inflammation and fibrosis was evaluated in these patients by examining liver biopsy specimens. Results: The levels of HBV DNA were >10,000 copies/ml in 58.4, 52.9 and 61.2% of the patients with traditional normal ALT, low normal ALT and high normal ALT values, respectively (p > 0.05). Also, the moderate degrees of hepatic necroinflammation [histological activity index (HAI)-NI score of ≧9] and severe hepatic fibrosis (HAI-F score of ≧3) were similar among the 3 groups of patients (p > 0.05). Conclusion: The newly defined low normal cutoff values for ALT did not exhibit any added clinical benefit for assessing the extent of liver damage in patients with chronic HBV infection in Bangladesh.

Significant histopathology in Chinese chronic hepatitis B patients with persistently high–normal alanine aminotransferase

Current guidelines recommend antiviral therapy for chronic hepatitis B (CHB) patients with elevated alanine aminotransferase (ALT) and high viral load. Scant histological data exist for CHB patients with persistently normal ALT (PNALT) because disease progression is thought to be rare. To identify potential predictors of significant histology in the presence of PNALT, we compared the clinical characteristics and histology of Chinese CHB PNALT patients to those in patients with elevated ALT. Percutaneous liver biopsy was performed in 522 CHB patients with Chinese ethnicity who had not had antiviral treatment. Differences in age, ALT, viral load, hepatitis B e antigen (HBeAg) status and liver histology were compared between eligible PNALT (252) and elevated ALT (270) patients. Of the PNALT patients, 38.5% had normal liver histology, 25.4% had significant necroinflammation and/or fibrosis and 8.4% had established cirrhosis. Furthermore, histopathological differences between patients with high-normal ALT (0.5-1.0 x the upper limit of normal (ULN)) and low-normal ALT (≤ 0.5 x ULN) were evaluated. There was a significantly greater prevalence of histopathology in the high-normal group (40.0%) than in the low-normal group (16.6%) (P < 0.001). Multiple logistic regression identified that significant histopathology findings in PNALT patients correlated with age (P < 0.001) and ALT level (P < 0.001), with age >40 years and ALT >0.5 x ULN predicting significant histopathology. Our data indicate that liver biopsy is recommended in CHB patients >40 years of age, particularly when their ALT is 0.5-1.0 x ULN. The findings above provide evidence for indication of antiviral therapy in patients with PNALT and significant histopathological change.

Prevalence and associated factors of non‐alcoholic fatty liver disease in patients with type‐2 diabetes mellitus

Diabetic patients have an increased prevalence and severity of non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the prevalence and the factors associated with the presence of ultrasonographic NAFLD in type-2 diabetic individuals. In a cross-sectional design study, 180 type-2 diabetic patients were submitted to a complete clinical and laboratory evaluation and abdominal ultrasonography for NAFLD detection and grading. Statistical analysis included bivariate tests, analysis of variance (anova, for increasing severity of steatosis) and multivariate logistic regression. The prevalence of ultrasonographic NAFLD was 69.4% [95% confidence interval (CI): 58.3-82.7%]. Patients with NAFLD were more obese, had a higher waist circumference and serum triglyceride and alanine aminotransferase (ALT) levels than those without steatosis. Neither diabetic degenerative complication, nor glycaemic control was associated with liver steatosis. On multivariate analysis, a high serum triglycerides level [>2.82 mmol/L, odds ratio (OR): 3.7-4.1, 95% CI: 1.2-13.3] and a high-normal ALT level (> or =40 U/L, OR: 2.5-2.7, 95% CI: 1.2-5.9) were independently associated with hepatic steatosis, together with either the presence of obesity (OR: 7.1, 95% CI: 3.0-17.0) or of increased waist circumference (OR: 4.8, 95% CI: 1.9-12.2). Type-2 diabetic patients have a high prevalence of ultrasonographic NAFLD and its presence is associated with obesity, mainly abdominal, hypertriglyceridaemia and high-normal ALT levels. Non-alcoholic fatty liver disease in diabetic patients may develop and progress independent of the diabetes progression itself.

Research of hepatic pathology and clinical characteristics of patients chronic infected with hepatitis B virus in immune tolerant stage

To investigate the characteristics of the hepatic pathological and clinical features of patients with hepatitis B virus (HBV) in immune tolerant stage and find the better measure of diagnosing patients chronic infected by HBV in immune tolerant phase. 135 patients with HBV chronic infection and persistently normal serum alanine aminotransferase (ALT) levels were involved in this study, whose serum HBeAg and HBV DNA were positive. Statistical analysis included the ages, sex, serum levels of HBVDNA, ALT and histological grade. The grades of inflammation and fibrosis were obtained through hepatic biopsy performed on all the patients. Mean age in those patients was 22.61 +/- 8.95 years old. All those patients were divided into two groups according to histological grade: low- histological grade group, G < or = 1 and S < or = 1; and high-histological grade group, G > or = 2, S > or = to 2. Levels of histological grade were low in most of patients (99/135). Patients of low-histological grade had no difference in age, sex and family history of HBsAg carriers. Compared with low-normal ALT (ALT less than 30U/L), those with high-normal ALT (ALT > or = 30U/L) had a greater frequencies of high-histological grade. Compared with high HBVDNA (HBVDNA > or = 10(7) copies/ml), those with low HBVDNA (HBVDNA less than 10(7) copies/ml) had a greater frequencies of high-histological grade. Levels of histological grade were low in most of patients with HBV chronic infection, serum HBeAg and HBVDNA positive, persistently normal serum ALT levels, but some of them were high-histological grade. It showed those patients were not all in immune tolerant stage of chronic HBV infection. Examination of ALT and HBVDNA are helpful to evaluate hepatic pathological damage for them.

Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values

A retrospective study was performed to (1) characterize the clinical and histologic features of those with nonalcoholic fatty liver disease (NAFLD) and normal alanine aminotransferase (ALT) values, (2) compare the spectrum of NAFLD associated with normal versus elevated ALT levels, and (3) determine whether there were differences in the clinical or histologic spectrum of NAFLD between those with a low normal versus high normal ALT value. A total of 51 subjects with NAFLD and normal ALT were identified and compared with 50 consecutive subjects with NAFLD and elevated ALT. The major indications for liver biopsy in those with normal ALT were unexplained hepatomegaly (n = 21) and evaluation as a potential donor for living donor liver transplantation (n = 16). The 2 groups were comparable with respect to age, gender distribution, and ethnicity. Approximately 80% of cases in both groups had at least 1 feature of the metabolic syndrome, the major risk factor for NAFLD. The 2 groups were also comparable with respect to the grade of the individual histologic parameters of NAFLD. A total of 12 subjects with normal ALT levels had bridging fibrosis, whereas 6 had cirrhosis. Diabetes was the only factor independently associated with an increased risk of advanced fibrosis (bridging fibrosis or cirrhosis) by multivariate analysis (relative risk: 2.3, P < .01). The mean steatosis (1.6 vs. 2.16, P < .04) and perisinusoidal fibrosis scores (0.35 vs. 0.9, P < .049) were lower in those with low normal (<30 IU/L) ALT versus high normal ALT. However, the prevalence of advanced fibrosis was similar (5 of 15 vs. 13 of 36, respectively). In conclusion, (1) the entire histologic spectrum of NAFLD can be seen in individuals with normal ALT values, (2) the histologic spectrum in these individuals is not significantly different from those with elevated ALT levels, and (3) a low normal ALT value does not guarantee freedom from underlying steatohepatitis with advanced fibrosis. (H epatology 2003;37:1286-1292.)