The epidemic of obesity has resulted in a parallel incremental burden of nonalcoholic fatty liver disease (NAFLD) worldwide. Nonalcoholic fatty liver disease includes a spectrum of liver disease that ranges from simple fat accumulation in the liver to necroinflammation, fibrosis, cirrhosis, and hepatocellular carcinoma, which in essence represent the stages of the natural history of NAFLD. The rising prevalence of NAFLD globally may be accounted for by changes in dietary habits and an increase in sedentary lifestyle. Nonalcoholic steatohepatitis (NASH), the aggressive form of NAFLD, is currently the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. In the current review, the authors discuss the uncertainty around the progression from NAFL (steatosis) to NASH (steatohepatitis), the undisputed progression of NASH to cirrhosis, and the risk factors that predispose to such progression. The published literature on the long-term cardiovascular complications and liver-related mortality of NAFLD is also discussed.

Epidemiology and Natural History of Nonalcoholic Fatty Liver Disease.

Background Although low alanine aminotransferase (ALT) levels have been associated with poor outcomes in the elderly population, the determinants subtending this association have been poorly explored. To gain insight into this topic, we analyzed data from a prospective population-based database (InCHIANTI study) in which frailty, disability, sarcopenia, and pyridoxine levels were systematically assessed. Methods Data are from 765 participants aged more than 65 years (mean age 75.3 years, women 61.8%), without chronic liver disease, malignancies, or alcohol abuse. Frailty was defined according to Fried criteria, sarcopenia through peripheral Quantitative-Computed-Tomography (lowest gender-specific tertile of the residuals of a linear regression of muscle mass from height and fat mass), and disability as self-reported need for help in at least one basic daily living activity. Associations of ALT with overall and cardiovascular mortality were assessed by Cox-models with time-dependent covariates. Results ALT activity was inversely associated with frailty, sarcopenia, disability, and pyridoxine deficiency; however, higher ALT was confirmed to be protective with respect of overall and cardiovascular mortality even in multiple-adjusted models including all these covariates (overall: hazard ratio [HR] 0.98 [0.96-1], p = .02; cardiovascular: 0.94 [0.9-0.98], p < .01). The association between ALT activity and mortality was nonlinear (J-shaped), and subjects in the lower quintiles of ALT levels showed a sharply increased overall and cardiovascular mortality. Conclusions These results suggest that reduced ALT levels in older individuals can be considered as a marker of frailty, disability, and sarcopenia, and as an independent predictor of adverse outcomes. The possible relationship between reduced ALT and impaired hepatic metabolic functions should be explored.

Low Alanine Aminotransferase Levels in the Elderly Population: Frailty, Disability, Sarcopenia, and Reduced Survival.

Measurement of serum alanine aminotransferase (ALT) is a common, readily available, and inexpensive laboratory assay in clinical practice. ALT activity is not only measured to detect liver disease, but also to monitor overall health. ALT activity is influenced by various factors, including viral hepatitis, alcohol consumption, and medication. Recently, the impact of metabolic abnormalities on ALT variation has raised concern due to the worldwide obesity epidemic. The normal ranges for ALT have been updated and validated considering the metabolic covariates in the various ethnic districts. The interaction between metabolic and demographic factors on ALT variation has also been discussed in previous studies. In addition, an extremely low ALT value might reflect the process of aging, and frailty in older adults has been raised as another clinically significant feature of this enzyme, to be followed with additional epidemiologic investigation. Timely updated, comprehensive, and systematic introduction of ALT activity is necessary to aid clinicians make better use of this enzyme.

/pdf/alanine-aminotransferase-old-biomarker-and-new-concept-a-32hz6ejohg.pdf

Alanine aminotransferase-old biomarker and new concept: a review.

Importance Increasing evidence suggests an important role of liver function in the pathophysiology of Alzheimer disease (AD). The liver is a major metabolic hub; therefore, investigating the association of liver function with AD, cognition, neuroimaging, and CSF biomarkers would improve the understanding of the role of metabolic dysfunction in AD. Objective To examine whether liver function markers are associated with cognitive dysfunction and the “A/T/N” (amyloid, tau, and neurodegeneration) biomarkers for AD. Design, Setting, and Participants In this cohort study, serum-based liver function markers were measured from September 1, 2005, to August 31, 2013, in 1581 AD Neuroimaging Initiative participants along with cognitive measures, cerebrospinal fluid (CSF) biomarkers, brain atrophy, brain glucose metabolism, and amyloid-β accumulation. Associations of liver function markers with AD-associated clinical and A/T/N biomarkers were assessed using generalized linear models adjusted for confounding variables and multiple comparisons. Statistical analysis was performed from November 1, 2017, to February 28, 2019. Exposures Five serum-based liver function markers (total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase) from AD Neuroimaging Initiative participants were used as exposure variables. Main Outcomes and Measures Primary outcomes included diagnosis of AD, composite scores for executive functioning and memory, CSF biomarkers, atrophy measured by magnetic resonance imaging, brain glucose metabolism measured by fludeoxyglucose F 18 (18F) positron emission tomography, and amyloid-β accumulation measured by [18F]florbetapir positron emission tomography. Results Participants in the AD Neuroimaging Initiative (n = 1581; 697 women and 884 men; mean [SD] age, 73.4 [7.2] years) included 407 cognitively normal older adults, 20 with significant memory concern, 298 with early mild cognitive impairment, 544 with late mild cognitive impairment, and 312 with AD. An elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio and lower levels of ALT were associated with AD diagnosis (AST to ALT ratio: odds ratio, 7.932 [95% CI, 1.673-37.617];P = .03; ALT: odds ratio, 0.133 [95% CI, 0.042-0.422];P = .004) and poor cognitive performance (AST to ALT ratio: β [SE], −0.465 [0.180];P = .02 for memory composite score; β [SE], −0.679 [0.215];P = .006 for executive function composite score; ALT: β [SE], 0.397 [0.128];P = .006 for memory composite score; β [SE], 0.637 [0.152];P  Conclusions and Relevance Consistent associations of serum-based liver function markers with cognitive performance and A/T/N biomarkers for AD highlight the involvement of metabolic disturbances in the pathophysiology of AD. Further studies are needed to determine if these associations represent a causative or secondary role. Liver enzyme involvement in AD opens avenues for novel diagnostics and therapeutics.

/pdf/association-of-altered-liver-enzymes-with-alzheimer-disease-59gwjnanyu.pdf

Association of Altered Liver Enzymes With Alzheimer Disease Diagnosis, Cognition, Neuroimaging Measures, and Cerebrospinal Fluid Biomarkers.

The relationships between blood tests of liver function and injury (alanine transaminase [ALT], gamma-glutamyl transferase, bilirubin, and albumin) with age, frailty, and survival were investigated in 1,673 community-dwelling men aged 70 years or older. ALT was lower in older participants. Those participants with ALT below the median at baseline had reduced survival (hazard ratio 2.10, 95% confidence interval [CI] 1.53-2.87) up to 4.9 years. Older age, frailty, low albumin, low body mass index, and alcohol abstinence also were associated with reduced survival, with age and frailty being the most powerful predictors. Low ALT was associated with frailty (odds ratio 3.54, 95% CI 2.45-5.11), and the relationship between ALT and survival disappeared once frailty and age were included in the survival analysis. Low ALT activity is a predictor of reduced survival; however, this seems to be mediated by its association with frailty and increasing age. ALT has potential value as a novel biomarker of aging.

/pdf/the-association-of-alanine-transaminase-with-aging-frailty-3o7f153xh0.pdf

The Association of Alanine Transaminase With Aging, Frailty, and Mortality

https://www.weizmann.ac.il/immunology/elinav/sites/immunology.elinav/files/2005_elinav_am_j_gastro.pdf

Correlation Between Serum Alanine Aminotransferase Activity and Age: An Inverted U Curve Pattern

Hepatitis C virus in various human body fluids: a systematic review

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Correlation Between Serum Alanine Aminotransferase Activity and Age: An Inverted U Curve Pattern

Hepatitis C virus in various human body fluids: a systematic review