Long-term exposure to air pollution and prevalent nonalcoholic fatty liver disease.

Background: Nonalcoholic fatty liver disease (NAFLD) is a disease characterized by lipid accumulation within hepatocytes, ranging from simple steatosis to steatohepatitis, in the absence of secondary causes of hepatic fat accumulation. Although air pollution (AP) has been associated with several conditions related to NAFLD (e.g., metabolic syndrome, type 2 diabetes mellitus), few studies have explored an association between AP and NAFLD. The aim of the study was to investigate whether exposure to AP is associated with NAFLD prevalence. Methods: We used baseline cross-sectional data (2000-2003) of the Heinz-Nixdorf-Recall cohort study in Germany (baseline n = 4,814), a prospective population-based cohort study in the urbanized Ruhr Area. Mean annual exposure to size-fractioned particulate matter (PM10, PM2.5, PMcoarse, and PM2.5abs), nitrogen dioxide, and particle number was assessed using two different exposure models: a chemistry transport dispersion model, which captures urban background AP exposure on a 1 km2 grid at participant's residential addresses, and a land use regression model, which captures point-specific AP exposure at participant's residential addresses. NAFLD was assessed with the fatty liver index (n = 4,065), with NAFLD defined as fatty liver index ≥60. We estimated ORs of NAFLD per interquartile range of exposure using logistic regression, adjusted for socio-demographic and lifestyle variables. Results: We observed a NAFLD prevalence of 31.7% (n = 1,288). All air pollutants were positively associated with NAFLD prevalence, with an OR per interquartile range for PM2.5 of 1.11 (95% confidence interval [CI] = 1.00, 1.24) using chemistry transport model, and 1.06 (95% CI = 0.94, 1.19) using the land use regression model, respectively. Conclusion: There was a positive association between long-term AP exposure and NAFLD.

Mitochondrial DNA methylation in metabolic associated fatty liver disease.

Introduction: Hepatic lipid accumulation and mitochondrial dysfunction are hallmarks of metabolic associated fatty liver disease (MAFLD), yet molecular parameters underlying MAFLD progression are not well understood. Differential methylation within the mitochondrial DNA (mtDNA) has been suggested to be associated with dysfunctional mitochondria, also during progression to Metabolic Steatohepatitis (MeSH). This study further investigates whether mtDNA methylation is associated with hepatic lipid accumulation and MAFLD. Methods: HepG2 cells were constructed to stably express mitochondria-targeted viral and prokaryotic cytosine DNA methyltransferases (mtM.CviPI or mtM.SssI for GpC or CpG methylation, respectively). A catalytically inactive variant (mtM.CviPI-Mut) was constructed as a control. Mouse and human patients' samples were also investigated. mtDNA methylation was assessed by pyro- or nanopore sequencing. Results and discussion: Differentially induced mtDNA hypermethylation impaired mitochondrial gene expression and metabolic activity in HepG2-mtM.CviPI and HepG2-mtM.SssI cells and was associated with increased lipid accumulation, when compared to the controls. To test whether lipid accumulation causes mtDNA methylation, HepG2 cells were subjected to 1 or 2 weeks of fatty acid treatment, but no clear differences in mtDNA methylation were detected. In contrast, hepatic Nd6 mitochondrial gene body cytosine methylation and Nd6 gene expression were increased in mice fed a high-fat high cholesterol diet (HFC for 6 or 20 weeks), when compared to controls, while mtDNA content was unchanged. For patients with simple steatosis, a higher ND6 methylation was confirmed using Methylation Specific PCR, but no additional distinctive cytosines could be identified using pyrosequencing. This study warrants further investigation into a role for mtDNA methylation in promoting mitochondrial dysfunction and impaired lipid metabolism in MAFLD.

Performance of the Liver Maximum Function Capacity Test, Fibrinogen, and Transient Elastography in Patients with Acute Liver Injury.

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. 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). RESULTS: The analysis included 34 patients (22 ALF, 12 AH; 19 males, 15 females; age 36.7 ± 14.6 years) with drug-induced liver injury (DILI) (n = 12), autoimmune hepatitis (AIH; n = 13), AIH-DILI overlap (n = 1), viral (n = 9), or cryptogenic liver failure (n = 1). Thirty-one patients recovered spontaneously, 2 patients died, and 1 patient underwent LT. The LiMAx was 197.6 (±68.4) for SR versus 92.33 (±65.0) for NSR (p = 0.0157). Fibrinogen was significantly lower in patients with NSR than in SR patients (209.0 vs. 106.3; p = 0.02). Mean liver stiffness measured by TE was 39.3 for NSR and 17.3 for SR (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. 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.

LiMAx Prior to Radioembolization for Hepatocellular Carcinoma as an Additional Tool for Patient Selection in Patients with Liver Cirrhosis.

BACKGROUND AND AIMS: Radioembolization (RE) has recently demonstrated a non-inferior survival outcome compared to systemic therapy for advanced hepatocellular carcinoma (HCC). Therefore, current guidelines recommend RE for patients with advanced HCC and preserved liver function who are unsuitable for transarterial chemoembolization (TACE) or systemic therapy. However, despite the excellent safety profile of RE, post-therapeutic hepatic decompensation remains a serious complication that is difficult to predicted by standard laboratory liver function parameters or imaging modalities. LiMAx® is a non-invasive test for liver function assessment, measuring the maximum metabolic capacity for 13C-Methacetin by the liver-specific enzyme CYP 450 1A2. Our study investigates the potential of LiMAx® for predicting post-interventional decompensation of liver function. PATIENTS AND METHODS: In total, 50 patients with HCC with or without liver cirrhosis and not amenable to TACE or systemic treatments were included in the study. For patients prospectively enrolled in our study, LiMAx® was carried out one day before RE (baseline) and 28 and 90 days after RE. Established liver function parameters were assessed at baseline, day 28, and day 90 after RE. The relationship between baseline LiMAx® and pre-and post-interventional liver function parameters, as well as the ability of LiMAx® to predict hepatic decompensation, were analyzed. RESULTS: We observed a strong association between baseline LiMAx® and bilirubin, albumin, ALBI grade, and MELD score. Patients presenting with Child-Pugh score B 28 days after RE or with a deterioration in Child-Pugh score by at least one point had a significantly lower baseline LiMAx® compared to those with Child-Pugh score A or with stable Child-Pugh score. The ability of LiMAx® to predict hepatic decompensation after RE was determined using ROC curve analysis and was compared to MELD score and ALBI grade. LiMAx® achieved a substantial AUC of 0.8117, comparable to MELD score and ALBI grade. CONCLUSION: Patients with lower LiMAx® values at baseline have a significantly increased risk for hepatic decompensation after RE, despite being categorized as Child-Pugh A. Therefore, LiMAx® can be used as an additional tool to identify patients at high risk of post-interventional hepatic failure.

Discovering Biomarkers for Non-Alcoholic Steatohepatitis Patients with and without Hepatocellular Carcinoma Using Fecal Metaproteomics.

High-calorie diets lead to hepatic steatosis and to the development of non-alcoholic fatty liver disease (NAFLD), which can evolve over many years into the inflammatory form of non-alcoholic steatohepatitis (NASH), posing a risk for the development of hepatocellular carcinoma (HCC). Due to diet and liver alteration, the axis between liver and gut is disturbed, resulting in gut microbiome alterations. Consequently, detecting these gut microbiome alterations represents a promising strategy for early NASH and HCC detection. We analyzed medical parameters and the fecal metaproteome of 19 healthy controls, 32 NASH patients, and 29 HCC patients, targeting the discovery of diagnostic biomarkers. Here, NASH and HCC resulted in increased inflammation status and shifts within the composition of the gut microbiome. An increased abundance of kielin/chordin, E3 ubiquitin ligase, and nucleophosmin 1 represented valuable fecal biomarkers, indicating disease-related changes in the liver. Although a single biomarker failed to separate NASH and HCC, machine learning-based classification algorithms provided an 86% accuracy in distinguishing between controls, NASH, and HCC. Fecal metaproteomics enables early detection of NASH and HCC by providing single biomarkers and machine learning-based metaprotein panels.

A Potential Role for Bile Acid Signaling in Celiac Disease-Associated Fatty Liver.

Celiac disease (CeD) is a chronic autoimmune disorder characterized by an intolerance to storage proteins of many grains. CeD is frequently associated with liver damage and steatosis. Bile acid (BA) signaling has been identified as an important mediator in gut-liver interaction and the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we aimed to analyze BA signaling and liver injury in CeD patients. Therefore, we analyzed data of 20 CeD patients on a gluten-free diet compared to 20 healthy controls (HC). We furthermore analyzed transaminase levels, markers of cell death, BA, and fatty acid metabolism. Hepatic steatosis was determined via transient elastography, by MRI and non-invasive scores. In CeD, we observed an increase of the apoptosis marker M30 and more hepatic steatosis as compared to HC. Fibroblast growth factor 19 (FGF19) was repressed in CeD, while low levels were associated with steatosis, especially in patients with high levels of anti-tissue transglutaminase antibodies (anti-tTG). When comparing anti-tTG-positive CeD patients to individuals without detectable anti-tTG levels, hepatic steatosis was accentuated. CeD patients with significant sonographic steatosis (defined by CAP ≥ 283 db/m) were exclusively anti-tTG-positive. In summary, our results suggest that even in CeD patients in clinical remission under gluten-free diet, alterations in gut-liver axis, especially BA signaling, might contribute to steatotic liver injury and should be further addressed in future studies and clinical practice.

Effects of Moderate Alcohol Consumption in Non-Alcoholic Fatty Liver Disease.

Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) have emerged as leading causes of chronic liver diseases worldwide. ALD and NAFLD share several pathophysiological patterns as well as histological features, while clinically, they are distinguished by the amount of alcohol consumed daily. However, NAFLD coexists with moderate alcohol consumption in a growing proportion of the population. Here, we investigated the effects of moderate alcohol consumption on liver injury, lipid metabolism, and gut microbiota in 30 NAFLD-patients. We anonymously assessed drinking habits, applying the AUDIT- and CAGE-questionnaires and compared subgroups of abstainers vs. low to harmful alcohol consumers (AUDIT) and Cage 0-1 vs. Cage 2-4. Patients who did not drink any alcohol had lower levels of γGT, ALT, triglycerides, and total cholesterol. While the abundance of Bacteroidaceae, Bifidobacteriaceae, Streptococcaceae, and Ruminococcaceae was higher in the low to harmful alcohol drinking cohort, the abundance of Rikenellaceae was higher in the abstainers. Our study suggests that even moderate alcohol consumption has an impact on the liver and lipid metabolism, as well as on the composition of gut microbiota.

Fat: Quality, or Quantity? What Matters Most for the Progression of Metabolic Associated Fatty Liver Disease (MAFLD).

OBJECTIVES: Lately, many countries have restricted or even banned transfat, and palm oil has become a preferred replacement for food manufacturers. Whether palm oil is potentially an unhealthy food mainly due to its high content of saturated Palmitic Acid (PA) is a matter of debate. The aim of this study was to test whether qualitative aspects of diet such as levels of PA and the fat source are risk factors for Metabolic Syndrome (MS) and Metabolic Associated Fatty Liver Disease (MAFLD). METHODS: C57BL/6 male mice were fed for 14 weeks with three types of Western diet (WD): 1. LP-WD-low concentration of PA (main fat source-corn and soybean oils); 2. HP-WD-high concentration of PA (main fat source-palm oil); 3. HP-Trans-WD-high concentration of PA (mainly transfat). RESULTS: All types of WD caused weight gain, adipocyte enlargement, hepatomegaly, lipid metabolism alterations, and steatohepatitis. Feeding with HP diets led to more prominent obesity, hypercholesterolemia, stronger hepatic injury, and fibrosis. Only the feeding with HP-Trans-WD resulted in glucose intolerance and elevation of serum transaminases. Brief withdrawal of WDs reversed MS and signs of MAFLD. However, mild hepatic inflammation was still detectable in HP groups. CONCLUSIONS: HP and HP-Trans-WD play a crucial role in the genesis of MS and MAFLD.

GALAD Score Detects Early-Stage Hepatocellular Carcinoma in a European Cohort of Chronic Hepatitis B and C Patients.

Despite vaccination programs and direct antiviral treatments, the incidence of virus-related hepatocellular carcinoma (HCC) remains high, while ultrasound-based detection rates for early-stage HCC is continuously low. To address this insufficiency, we set out to characterize whether the GALAD score, which incorporates gender, age, and serum levels of AFP, AFP isoform L3 (AFP-L3), and des-gamma-carboxy-prothrombin (DCP), can improve early-stage HCC detection in a Caucasian HBV/HCV cohort. In a retrospective German single-center study, 182 patients with HBV, 223 with HCV and 168 with other etiology (OE) of chronic liver disease (CLD) were enrolled. HCC was confirmed in 52 HBV, 84 HCV and 60 OE CLD patients. The diagnostic performance of the single biomarkers in HCC detection was compared to the GALAD model. At initial diagnosis, most patients were at (very) early BCLC 0 (n = 14/7%) or A (n = 56/29%) or intermediate stage BCLC B (n = 93/47%) HCC in all three subgroups. In the BCLC 0/A cohort, GALAD exhibited an AUC of 0.94 discriminating HCC from non-HCC, surpassing AFP (AUC 0.86), AFP-L3 (AUC 0.83) and DCP (AUC 0.83). In the HBV population, GALAD achieved an AUC of 0.96, in HCV an AUC of 0.98 and in OE an AUC of 0.99, clearly superior to the biomarkers alone. Furthermore, in HCV patients GALAD showed a significantly higher specificity (89%) versus AFP (64%) alone. In chronic viral hepatitis, the GALAD model showed superior performance in detection of early-stage HCC, while exhibiting higher specificity in HCV patients compared to AFP alone. We conclude that the GALAD score shows potential for HCC surveillance in Caucasian HBV/HCV patients.

Anti-TNFα treatment in Crohn's disease: Impact on hepatic steatosis, gut-derived hormones and metabolic status.

BACKGROUND AND AIMS: An association between Crohn's disease (CD) and hepatic steatosis has been reported. However, the underlying mechanisms of steatosis progression in CD are not clear. Among the most effective CD treatments are agents that inhibit Tumor-Necrosis-Factor (TNF) activity, yet it is unclear why anti-TNFα agents would affect steatosis in CD. Recent studies suggest that microbiome can affect both, CD and steatosis pathogenesis. Therefore, we here analysed a potential relationship between anti-TNF treatment and hepatic steatosis in CD, focusing on the gut-liver axis. METHODS: This cross-sectional study evaluated patients with established CD, with and without anti-TNFα treatment, analysing serum markers of liver injury, measurement of transient elastography, controlled attenuation parameter (CAP) and MRI for fat detection. Changes in lipid and metabolic profiles were assessed by serum and stool lipidomics and metabolimics. Additionally, we analysed gut microbiota composition and mediators of bile acid (BA) signalling via stool and serum analysis. RESULTS: Patients on anti-TNFα treatment had less hepatic steatosis as assessed by CAP and MRI. Serum FGF19 levels were significantly higher in patients on anti-TNFα therapy and associate with reduced steatosis and increased bowel motility. Neutral lipids including triglycerides were reduced in the serum of patients on anti-TNF treatment. Bacteria involved in BA metabolism and FGF19 regulation, including Firmicutes, showed group-specific alterations with low levels in patients without anti-TNFα treatment. Low abundance of Firmicutes was associated with higher triglyceride levels. CONCLUSIONS: Anti-TNFα treatment is associated with reduced steatosis, lower triglyceride levels, alterations in FXR-signalling (eg FGF19) and microbiota composition in CD.

Simultaneous Induction of Glycolysis and Oxidative Phosphorylation during Activation of Hepatic Stellate Cells Reveals Novel Mitochondrial Targets to Treat Liver Fibrosis.

Upon liver injury, hepatic stellate cells (HSCs) transdifferentiate to migratory, proliferative and extracellular matrix-producing myofibroblasts (e.g., activated HSCs; aHSCs) causing liver fibrosis. HSC activation is associated with increased glycolysis and glutaminolysis. Here, we compared the contribution of glycolysis, glutaminolysis and mitochondrial oxidative phosphorylation (OXPHOS) in rat and human HSC activation. Basal levels of glycolysis (extracellular acidification rate ~3-fold higher) and particularly mitochondrial respiration (oxygen consumption rate ~5-fold higher) were significantly increased in rat aHSCs, when compared to quiescent rat HSC. This was accompanied by extensive mitochondrial fusion in rat and human aHSCs, which occurred without increasing mitochondrial DNA content and electron transport chain (ETC) components. Inhibition of glycolysis (by 2-deoxy-D-glucose) and glutaminolysis (by CB-839) did not inhibit rat aHSC proliferation, but did reduce Acta2 (encoding α-SMA) expression slightly. In contrast, inhibiting mitochondrial OXPHOS (by rotenone) significantly suppressed rat aHSC proliferation, as well as Col1a1 and Acta2 expression. Other than that observed for rat aHSCs, human aHSC proliferation and expression of fibrosis markers were significantly suppressed by inhibiting either glycolysis, glutaminolysis or mitochondrial OXPHOS (by metformin). Activation of HSCs is marked by simultaneous induction of glycolysis and mitochondrial metabolism, extending the possibilities to suppress hepatic fibrogenesis by interfering with HSC metabolism.

Hepatocyte KLF6 expression affects FXR signalling and the clinical course of primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is characterized by chronic cholestasis and inflammation, which promotes cirrhosis and an increased risk of cholangiocellular carcinoma (CCA). The transcription factor Krueppel-like-factor-6 (KLF6) is a mediator of liver regeneration, steatosis, and hepatocellular carcinoma (HCC), but no data are yet available on its potential role in cholestasis. Here, we aimed to identify the impact of hepatic KLF6 expression on cholestatic liver injury and PSC and identify potential effects on farnesoid-X-receptor (FXR) signalling. METHODS: Hepatocellular KLF6 expression was quantified by immunohistochemistry (IHC) in liver biopsies of PSC patients and correlated with serum parameters and clinical outcome. Liver injury was analysed in hepatocyte-specific Klf6-knockout mice following bile duct ligation (BDL). Chromatin-immunoprecipitation-assays (ChIP) and KLF6-overexpressing HepG2 cells were used to analyse the interaction of KLF6 and FXR target genes such as NR0B2. RESULTS: Based on IHC, PSC patients could be subdivided into two groups showing either low (<80%) or high (>80%) hepatocellular KLF6 expression. In patients with high KLF6 expression, we observed a superior survival in Kaplan-Meier analysis. Klf6-knockout mice showed reduced hepatic necrosis following BDL when compared to controls. KLF6 suppressed NR0B2 expression in HepG2 cells mediated through binding of KLF6 to the NR0B2 promoter region. CONCLUSION: Here, we show an association between KLF6 expression and the clinical course and overall survival in PSC patients. Mechanistically, we identified a direct interaction of KLF6 with the FXR target gene NR0B2.

Altered Microbiota Diversity and Bile Acid Signaling in Cirrhotic and Noncirrhotic NASH-HCC.

OBJECTIVES: The precipitous increase in nonalcoholic steatohepatitis (NASH) is accompanied by a dramatic increase in the incidence of NASH-related hepatocellular carcinoma (HCC). HCC in NASH has a higher propensity to arise without pre-existing cirrhosis compared with other chronic liver diseases. METHODS: To identify the potential links between liver and gut in NASH-related hepatocarcinogenesis, we compared the gut microbiota and mediators of bile acid (BA) signaling in the absence or presence of cirrhosis through the analysis of stool and serum samples from patients with NASH non-HCC and NASH-HCC and healthy volunteers. RESULTS: Serum levels of total and individual BA were higher in NASH compared with healthy controls. Furthermore, serum levels of the primary conjugated BAs glycine-conjugated cholic acid, taurine-conjugated cholic acid, glycine-conjugated chenodeoxycholic acid, and taurine-conjugated chenodeoxycholic acid were significantly increased in cirrhotic vs noncirrhotic patients, independent of the occurrence of HCC. By contrast, serum FGF19 levels were higher in patients with NASH-HCC and associated with tumor markers as well as an attenuation of BA synthesis. Specific alterations in the gut microbiome were found for several bacteria involved in the BA metabolism including Bacteroides and Lactobacilli. Specifically, the abundance of Lactobacilli was associated with progressive disease, serum BA levels, and liver injury in NASH and NASH-HCC. DISCUSSION: Here, we demonstrate a clear association of the altered gut microbiota and primary conjugated BA composition in cirrhotic and noncirrhotic patients with NASH-HCC. Microbiota-associated alterations in BA homeostasis and farnesoid X receptor signaling, via FGF19, might thus contribute to fibrogenesis, liver injury, and tumorigenesis in NASH-HCC.

Intestinal Epithelial Cell-Derived Extracellular Vesicles Modulate Hepatic Injury via the Gut-Liver Axis During Acute Alcohol Injury.

Binge drinking, i.e., heavy episodic drinking in a short time, has recently become an alarming societal problem with negative health impact. However, the harmful effects of acute alcohol injury in the gut-liver axis remain elusive. Hence, we focused on the physiological and pathological changes and the underlying mechanisms of experimental binge drinking in the context of the gut-liver axis. Eight-week-old mice with a C57BL/6 background received a single dose (p.o.) of ethanol (EtOH) [6 g/kg b.w.] as a preclinical model of acute alcohol injury. Controls received a single dose of PBS. Mice were sacrificed 8 h later. In parallel, HepaRGs and Caco-2 cells, human cell lines of differentiated hepatocytes and intestinal epithelial cells intestinal epithelial cells (IECs), respectively, were challenged in the presence or absence of EtOH [0-100 mM]. Extracellular vesicles (EVs) isolated by ultracentrifugation from culture media of IECs were added to hepatocyte cell cultures. Increased intestinal permeability, loss of zonula occludens-1 (ZO-1) and MUCIN-2 expression, and alterations in microbiota-increased Lactobacillus and decreased Lachnospiraceae species-were found in the large intestine of mice exposed to EtOH. Increased TUNEL-positive cells, infiltration of CD11b-positive immune cells, pro-inflammatory cytokines (e.g., tlr4, tnf, il1ß), and markers of lipid accumulation (Oil Red O, srbep1) were evident in livers of mice exposed to EtOH, particularly in females. In vitro experiments indicated that EVs released by IECs in response to ethanol exerted a deleterious effect on hepatocyte viability and lipid accumulation. Overall, our data identified a novel mechanism responsible for driving hepatic injury in the gut-liver axis, opening novel avenues for therapy.

GALAD Score Detects Early Hepatocellular Carcinoma in an International Cohort of Patients With Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: The prevalence of nonalcoholic steatohepatitis (NASH) associated hepatocellular carcinoma (HCC) is increasing. However, strategies for detection of early-stage HCC in patients with NASH have limitations. We assessed the ability of the GALAD score, which determines risk of HCC based on patient sex; age; and serum levels of α-fetoprotein (AFP), AFP isoform L3 (AFP-L3), and des-gamma-carboxy prothrombin (DCP), to detect HCC in patients with NASH. METHODS: We performed a case-control study of 125 patients with HCC (20% within Milan Criteria) and 231 patients without HCC (NASH controls) from 8 centers in Germany. We compared the performance of serum AFP, AFP-L3, or DCP vs GALAD score to identify patients with HCC using receiver operating characteristic curves and corresponding area under the curve (AUC) analyses. We also analyzed data from 389 patients with NASH under surveillance for HCC in Japan, followed for a median of 167 months. During the 5-year screening period, 26 patients developed HCC. To compensate for irregular intervals of data points, we performed locally weighted scatterplot smoothing, linear regression, and a non-linear curve fit to assess development of GALAD before HCC development. RESULTS: The GALAD score identified patients with any stage HCC with an AUC of 0.96 - significantly greater than values for serum levels of AFP (AUC, 0.88), AFP-L3 (AUC, 0.86) or DCP (AUC, 0.87). AUC values for the GALAD score were consistent in patients with cirrhosis (AUC, 0.93) and without cirrhosis (AUC, 0.98). For detection of HCC within Milan Criteria, the GALAD score achieved an AUC of 0.91, with a sensitivity of 68% and specificity of 95% at a cutoff of -0.63. In a pilot Japanese cohort study, the mean GALAD score was higher in patients with NASH who developed HCC than in those who did not develop HCC as early as 1.5 years before HCC diagnosis. GALAD scores were above -0.63 approximately 200 days before the diagnosis of HCC. CONCLUSIONS: In a case-control study performed in Germany and a pilot cohort study in Japan, we found the GALAD score may detect HCC with high levels of accuracy in patients with NASH, with and without cirrhosis. The GALAD score can detect patients with early-stage HCC, and might facilitate surveillance of patients with NASH, who are often obese, which limits the sensitivity of detection of liver cancer by ultrasound.

NAFLD-Associated Comorbidities in Advanced Stage HCC Do Not Alter the Safety and Efficacy of Yttrium-90 Radioembolization.

BACKGROUND: Patients with advanced hepatocellular carcinoma (HCC) arising in nonalcoholic fatty liver disease (NAFLD) may not be suitable for systemic therapy due to metabolic syndrome-related diseases. Recent trials did not show a survival benefit of radioembolization (RE) compared to sorafenib in advanced stage HCC but RE may represent an adequate alternative in patients with contraindications to systemic therapy due to its favorable safety profile. AIM: To investigate the impact of NAFLD-related comorbidities on safety and efficacy of RE for HCC treatment in a retrospective monocentric cohort study. PATIENTS AND METHODS: Safety and efficacy of RE were evaluated in patients with NAFLD-associated HCC. Hepatitis B virus (HBV)-related HCC patients served as controls, exhibiting matching Barcelona Liver Cancer Clinic (BCLC) stages while showing significantly fewer metabolic comorbidities. RESULTS: Overall, 87 HCC patients with NAFLD (mean age 71.3 ± 6.9 years) and 62 HCC patients with HBV (mean age 58.8 ± 10.9 years) not amenable to surgical or conventional locoregional treatments were included. Patients with HBV-related HCC had a comparable liver function to HCC patients with NAFLD. RE treatment-related toxicity did not differ between the two groups (increase in bilirubin Common Terminology Criteria for Adverse Events grade in 29 [38.7%] NAFLD and 20 [39.2%] HBV patients, p = 0.91). Overall survival was similar in HCC patients with NAFLD and HBV (11.1 [interquartile range, IQR, 18.27] vs. 9.3 months [IQR 14.73], p = 0.38), also in the subgroup analyses of BCLC B and C stages. CONCLUSION: RE showed similar survival outcomes at a comparable toxicity profile in HCC patients with NAFLD and HBV. NAFLD-associated metabolic comorbidities did not exhibit limitations for RE while offering comparable therapeutic efficacy as compared to HBV patients.

Low Free Triiodothyronine Is Associated with Advanced Fibrosis in Patients at High Risk for Nonalcoholic Steatohepatitis.

BACKGROUND: Thyroid hormone is critical for tissue-organ development, growth, differentiation, and metabolism. In murine models of advanced nonalcoholic steatohepatitis (NASH), the administration of T3 reduced liver triglyceride, repressed liver inflammation, and attenuated injury. In recent studies of patients with NASH, hypothyroidism was noted to be associated with more advanced NASH. These findings suggest that thyroid hormone function might be a modulator of nonalcoholic fatty liver disease (NAFLD) outcomes. AIMS: Herein, we evaluated the correlation between plasma TSH/free T3 (fT3)/free T4 (fT4) levels and (non-invasive) surrogate markers of NAFLD fibrosis. METHODS: We performed a retrospective analysis of 144 patients who were seen in our NASH outpatient clinic between 2015 and 2017. Each patient underwent a standard anthropometric assessment, laboratory and clinical evaluations, and liver stiffness measurements by transient elastography (Fibroscan). Univariate analysis and multivariate linear and logistic regression analysis were used to identify factors independently associated with NASH and advanced fibrosis. RESULTS: Low fT3 values but not TSH and fT4 were associated with higher liver stiffness and higher NAFLD fibrosis score, respectively. fT3 and TSH values correlated significantly with indices of liver disease including INR, albumin, ALT, AST, bilirubin, and platelets. In multivariate analyses, a low fT3 was independently associated with high NFS scores (OR 0.169, CI 0.05-0.54, p = 0.003) and was also associated with high liver stiffness readings (OR 0.326, CI 0.135-0.785, p = 0.001). CONCLUSION: A low-normal thyroid hormone function is predictive of NASH and advanced fibrosis and may have a pathogenic role in modulating NAFLD outcomes.