Patterns and predictors of mortality and disease progression among patients with non-alcoholic fatty liver disease

\(\bf Background: Factors associated with mortality and disease progression in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are poorly understood. \(\bf Aims: To assess the impact of liver disease severity, demographics and comorbidities on all-cause mortality and liver disease progression in a large, real-world cohort of NAFLD patients. \(\bf Methods: Claims data from the German Institut für angewandte Gesundheitsforschung database between 2011 and 2016 were analyzed retrospectively. Adult patients diagnosed with NAFLD and/or NASH were categorised as NAFLD, NAFLD nonprogressors, compensated cirrhosis, decompensated cirrhosis, liver transplant or hepatocellular carcinoma (HCC). The longitudinal probability of mortality and incidence of progression were calculated for disease severity cohorts and multivariable analyses performed for adjusted mortality. \(\bf Results: Among 4 580 434 patients in the database, prevalence of NAFLD was 4.7% (n = 215 655). Of those, 36.8% were non-progressors, 0.2% compensated cirrhosis, 9.6% decompensated cirrhosis, 0.0005% liver transplant and 0.2% HCC. Comorbidity rates were significantly higher in compensated cirrhosis, decompensated cirrhosis and HCC compared with non-progressors. The longitudinal probability of mortality for non-progressors, compensated cirrhosis, decompensated cirrhosis and HCC was 3.6%, 18.7%, 28.8% and 68%, respectively. Independent predictors of mortality included cardiovascular disease, type 2 diabetes mellitus, hypertension, obesity and renal impairment. The cumulative incidence of progression in NAFLD and compensated cirrhosis patients was 10.7% and 16.7%, respectively, over 5 years of follow-up. \(\bf Conclusion: NAFLD patients were severely under-diagnosed and had a high probability of mortality that increased with disease progression. Early identification and effective management to halt or reverse fibrosis are essential to prevent progression

Transcriptome-wide analysis of human liver reveals age-related differences in the expression of select functional gene clusters and evidence for a PPP1R10\it PPP1R10-governed "aging cascade"

A transcriptome-wide analysis of human liver for demonstrating differences between young and old humans has not yet been performed. However, identifying major age-related alterations in hepatic gene expression may pinpoint ontogenetic shifts with important hepatic and systemic consequences, provide novel pharmacogenetic information, offer clues to efficiently counteract symptoms of old age, and improve the overarching understanding of individual decline. Next-generation sequencing (NGS) data analyzed by the Mann–Whitney nonparametric test and Ensemble Feature Selection (EFS) bioinformatics identified 44 transcripts among 60,617 total and 19,986 protein-encoding transcripts that significantly ($\it p$ = 0.0003 to 0.0464) and strikingly (EFS score > 0.3:16 transcripts; EFS score > 0.2:28 transcripts) differ between young and old livers. Most of these age-related transcripts were assigned to the categories "regulome", "inflammaging", "regeneration", and "pharmacogenes". NGS results were confirmed by quantitative real-time polymerase chain reaction. Our results have important implications for the areas of ontogeny/aging and the age-dependent increase in major liver diseases. Finally, we present a broadly substantiated and testable hypothesis on a genetically governed "aging cascade!, wherein $\it PPP1R10$ acts as a putative ontogenetic master regulator, prominently flanked by $\it IGFALS$ and $\it DUSP1$. This transcriptome-wide analysis of human liver offers potential clues towards developing safer and improved therapeutic interventions against major liver diseases and increased insights into key mechanisms underlying aging

Significance of simple steatosis

Non-alcoholic fatty liver disease (NAFLD) is defined clinicopathologically by the accumulation of lipids in >5% of hepatocytes and the exclusion of secondary causes of fat accumulation. NAFLD encompasses a wide spectrum of liver damage, extending from simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH)-the latter is characterized by inflammation and hepatocyte ballooning degeneration, in addition to the steatosis, with or without fibrosis. NAFLD is now the most common cause of chronic liver disease in Western countries and affects around one quarter of the general population. It is a multisystem disorder, which is associated with an increased risk of type 2 diabetes mellitus as well as liver- and cardiovascular-related mortality. Although earlier studies had suggested that NAFL is benign (i.e., non-progressive), cumulative evidence challenges this dogma, and recent data suggest that nearly 25% of those with NAFL may develop fibrosis. Importantly, NAFLD patients are more susceptible to the toxic effects of alcohol, drugs, and other insults to the liver. This is likely due to the functional impairment of steatotic hepatocytes, which is virtually undetectable by current clinical tests. This review provides an overview of the current evidence on the clinical significance of NAFL and discusses the molecular basis for NAFL development and progression

Lipoprotein and Metabolic Profiles Indicate Similar Cardiovascular Risk of Liver Steatosis and NASH

$\textit {Background and Aim}$: Nonalcoholic fatty liver disease (NAFLD) affects about 25% of the global population, with no reliable noninvasive tests to diagnose nonalcoholic steatohepatitis (NASH) and to differentiate between NASH and nonalcoholic fatty liver (NAFL) (steatosis alone). It is unclear if NAFL and NASH differ in cardiovascular risk for patients. Here, we compared obese NAFLD patients with a healthy cohort to test whether cholesterol compounds could represent potential noninvasive markers and to estimate associated risks. $\it Method:$ Serum samples of 46 patients with histologically confirmed NAFLD (17 NAFL, 29 NASH) who underwent bariatric surgery were compared to 32 (9 males, 21 females) healthy controls (HCs). We analyzed epidemiological data, liver enzymes, cholesterol and lipid profile, and amino acids. The latter were analyzed by nuclear magnetic resonance spectroscopy. $\it Results:$ Total serum and high-density lipoprotein (HDL) cholesterol were significantly lower in the NAFLD group than in HCs, with a stronger reduction in NASH. Similar observations were made for sub-specification of HDL-p, HDL-s, SHDL-p, and LHDL-p cholesterols. Low-density lipoprotein (LDL)-s and LLDL-p cholesterol were significantly reduced in NAFLD groups. Interestingly, SLDL-p cholesterol was significantly higher in the NAFL group with a stronger elevation in NASH than in HCs. The amino acids alanine, leucin, and isoleucine were significantly higher in the NAFL and NASH groups than in HCs. $\it Conclusion:$ We show in this study that cholesterol profiles, apolipoproteins, and amino acids could function as a potential noninvasive test to screen for NAFLD or even NASH in larger populations. However, few differences in cholesterol profiles were identified between the NAFL and NASH groups, indicating similar cardiovascular risk profiles

Transaminase concentrations cannot separate non-alcoholic fatty liver and non-alcoholic steatohepatitis in morbidly obese patients irrespective of histological algorithm

$\bf Background:$ In current general practice, elevated serum concentrations of liver enzymes are still regarded as an indicator of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In this study, we analyzed if an adjustment of the upper limit of normal (ULN) for serum liver enzymes can improve their diagnostic accuracy. $\bf Methods:$ Data from 363 morbidly obese patients (42.5 $\pm$ 10.3 years old; mean BMI: 52 $\pm$ 8.5 kg/m$^{2}$), who underwent bariatric surgery, was retrospectively analyzed. NAFL and NASH were defined histologically according to non-alcoholic fatty liver activity score (NAS) and according to steatosis activity fibrosis (SAF) score for 2 separate analyses, respectively. $\bf Results:$ In 121 women (45%) and 45 men (46%), elevated values for at least one serum parameter (ALT, AST, $\gamma$GT) were present. The serum concentrations of ALT ($\it p$ < 0.0001), AST ($\it p$ < 0.0001) and $\gamma$GT ($\it p$ = 0.0023) differed significantly between NAFL and NASH, irrespective of the applied histological classification method. Concentrations of all 3 serum parameters correlated significantly positively with the NAS and the SAF score, with correlation coefficients between 0.33 (ALT/NAS) and 0.40 ($\gamma$GT/SAF). The area under the curves to separate NAFL and NASH by liver enzymes achieved a maximum of 0.70 (ALT applied to NAS-based classification). For 95% specificity, the ULN for ALT would be 47.5 U/L; for 95% sensitivity, the ULN for ALT would be 17.5 U/L, resulting in 62% uncategorized patients. $\bf Conclusion:$ ALT, AST, and γGT are unsuitable for non-invasive screening or diagnosis of NAFL or NASH. Utilizing liver enzymes as an indicator for NAFLD or NASH should generally be questioned

Performance of the liver maximum function capacity test, fibrinogen, and transient elastography in patients with acute liver injury

$\bf Background:$ Acute liver failure (ALF) occurs as a rare, sudden, extensive loss of liver function in a previously healthy liver. In advanced cases, ALF may require liver transplantation (LT). Available prognostic parameters have limited accuracy to decide, which patient to consider for LT. The liver maximum function capacity test (LiMAx) can accurately determine liver function and was assessed as predictor of survival, along with coagulation parameters and liver stiffness in nonacetaminophen-induced ALF. $\bf Methods:$ Various liver function tests, including LiMAx measurements, coagulation factors, and transient elastography (TE), were analyzed retrospectively for associations with clinical outcome in 34 patients with ALF or acute hepatitis (AH). Data were compared between patients with spontaneous recovery (SR) and non-SR (3-month mortality/LT; NSR). $\bf Results:$ The analysis included 34 patients (22 ALF, 12 AH; 19 males, 15 females; age 36.7 $\pm$ 14.6 years) with drug-induced liver injury (DILI) ($\it n$ = 12), autoimmune hepatitis (AIH; $\it n$ = 13), AIH-DILI overlap ($\it n$ = 1), viral ($\it n$ = 9), or cryptogenic liver failure ($\it n$ = 1). Thirty-one patients recovered spontaneously, 2 patients died, and 1 patient underwent LT. The LiMAx was 197.6 ($\pm$68.4) for SR versus 92.33 ($\pm$65.0) for NSR ($\it p$ = 0.0157). Fibrinogen was significantly lower in patients with NSR than in SR patients (209.0 vs. 106.3; $\it p$ = 0.02). Mean liver stiffness measured by TE was 39.3 for NSR and 17.3 for SR ($\it p$ = 0.26). KCC was fulfilled in only 4 patients (3 SR, 1 NSR). LiMAx results correlated positively with serum fibrinogen and antithrombin III concentrations and correlated negatively with liver stiffness. No other analyzed factor could differentiate between SR and NSR. $\bf Conclusion:$ Decision-making in ALF remains challenging. LiMAx and fibrinogen might predict the prognosis in patients with nonacetaminophen-induced ALF and in combination could be feasible tools to decide if LT is necessary