Bile acids associate with specific gut microbiota, low-level alcohol consumption and liver fibrosis in patients with non-alcoholic fatty liver disease.

BACKGROUND: Bile acids (BAs) are synthesized by the liver and modified by gut bacteria, and may play an intermediary role between the gut microbiome and liver in promoting fibrosis in non-alcoholic fatty liver disease (NAFLD). We investigated the associations between serum and faecal BAs, gut microbiome and fibrosis in patients with and without NAFLD and examined the impact of diet and alcohol consumption on these relationships. METHODS: Adult patients (n = 122) underwent liver biopsy and BAs characterization by high-performance liquid chromatography/mass spectrometry. Gut microbiome composition was analysed using next-generation 16S rRNA sequencing. Diet and alcohol intake were determined by 3-day food diary. RESULTS: Serum and faecal BA concentrations increased progressively among non-NAFLD controls (n = 55), NAFLD patients with no/mild fibrosis (F0-2, n = 58) and NAFLD with advanced fibrosis (F3/4, n = 9). Progressive increases in serum BAs were driven by primary conjugated BAs including glycocholic acid [GCA] and secondary conjugated BAs. In contrast, faecal BA increase was driven by secondary unconjugated BAs (predominately deoxycholic acid [DCA]). Serum GCA levels and faecal DCA levels correlated with the abundance of Bacteroidaceae and Lachnospiraceae, and stool secondary BAs with an unclassifiable family of the order Bacteroidales (Bacteroidales;other). These bacterial taxa were also associated with advanced fibrosis. Modest alcohol consumption was positively correlated with faecal DCA levels and relative abundance of Lachnospiracaea and Bacteroidales;other. CONCLUSIONS: Higher serum and faecal BA levels are associated with advanced fibrosis in NAFLD. Specific gut bacteria link alterations in BA profiles and advanced fibrosis, and may be influenced by low-level alcohol consumption.

Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease.

Rodent and cell-culture models support a role for iron-related adipokine dysregulation and insulin resistance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); however, substantial human data are lacking. We examined the relationship between measures of iron status, adipokines, and insulin resistance in patients with NAFLD in the presence and absence of venesection. This study forms part of the Impact of Iron on Insulin Resistance and Liver Histology in Nonalcoholic Steatohepatitis (IIRON2) study, a prospective randomized controlled trial of venesection for adults with NAFLD. Paired serum samples at baseline and 6 months (end of treatment) in controls (n = 28) and patients who had venesection (n = 23) were assayed for adiponectin, leptin, resistin, retinol binding protein-4, tumor necrosis factor α, and interleukin-6, using a Quantibody, customized, multiplexed enzyme-linked immunosorbent assay array. Hepatic iron concentration (HIC) was determined using MR FerriScan. Unexpectedly, analysis revealed a significant positive correlation between baseline serum adiponectin concentration and HIC, which strengthened after correction for age, sex, and body mass index (rho = 0.36; P = 0.007). In addition, there were significant inverse correlations between HIC and measures of insulin resistance (adipose tissue insulin resistance (Adipo-IR), serum insulin, serum glucose, homeostasis model assessment of insulin resistance, hemoglobin A1c, and hepatic steatosis), whereas a positive correlation was noted with the insulin sensitivity index. Changes in serum adipokines over 6 months did not differ between the control and venesection groups. Conclusion: HIC positively correlates with serum adiponectin and insulin sensitivity in patients with NAFLD. Further study is required to establish causality and mechanistic explanations for these associations and their relevance in the pathogenesis of insulin resistance and NAFLD. (Hepatology Communications 2018;2:644-653).

Type and Pattern of Alcohol Consumption is Associated With Liver Fibrosis in Patients With Non-alcoholic Fatty Liver Disease.

INTRODUCTION: It is unclear whether low levels of alcohol are harmful in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to determine whether quantity, binge pattern consumption, or type of alcohol was associated with liver fibrosis in patients with NAFLD. METHODS: Previous and current alcohol consumption was assessed in NAFLD patients undergoing liver biopsy. All subjects currently consumed <210 g per week (male) or <140 g per week (female). Binge consumption was defined as ≥4 standard drinks (female) or ≥5 standard drinks (male) in one sitting. Liver biopsies were scored according to the NASH CRN system with F3/4 fibrosis defined as advanced. RESULTS: Among 187 patients (24% with advanced fibrosis), the median weekly alcohol consumption was 20 (2.3-60) g over an average of 18 years. Modest consumption (1-70 g per week) was associated with lower mean fibrosis stage compared to lifetime abstainers (p < 0.05) and a decreased risk of advanced fibrosis (OR 0.33, 95% CI 0.14-0.78, p = 0.01). The association with reduced fibrosis was not seen in subjects drinking in a binge-type fashion. Exclusive wine drinkers but not exclusive beer drinkers, had lower mean fibrosis stage and lower odds of advanced fibrosis (OR 0.20, 95% CI 0.06-0.69, p = 0.01), compared to lifetime abstinent subjects. No interaction between gender and alcohol quantity, type, or binge consumption on fibrosis was observed. DISCUSSION: Modest (1-70 g per week) alcohol consumption, particularly wine in a non-binge pattern, is associated with lower fibrosis in patients with NAFLD. Prospective longitudinal studies into fibrosis progression, cardiovascular outcomes, and mortality are required before clinical recommendations can be made.

Nonalcoholic fatty liver disease-related cirrhosis is commonly unrecognized and associated with hepatocellular carcinoma.

Determination of cirrhosis in nonalcoholic fatty liver disease (NAFLD) is important as it alters prognosis and management. We aimed to examine whether cirrhosis was diagnosed incidentally or intentionally in patients with NAFLD. We reviewed 100 patients with NAFLD cirrhosis to determine mode of cirrhosis diagnosis (incidental or by intent), severity of liver disease at diagnosis, diagnostician, and previous clinical imaging or laboratory evidence of unrecognized cirrhosis. The majority (66/100) of patients with NAFLD cirrhosis were diagnosed incidentally, with the majority of these (74%) diagnosed with NAFLD simultaneously. Those with incidental cirrhosis diagnoses had more deranged platelet and international normalized ratio levels (P < 0.05) and were more likely to have concomitant hepatocellular carcinoma (HCC) (12% versus 0%, P < 0.05). Incidental cirrhosis was diagnosed following imaging (32%) or liver tests (26%) performed for reasons unrelated to liver disease, following unexpected endoscopic finding of varices (21%) or an unexpected surgical finding (14%). Diagnoses by intent were predominantly made by gastroenterologists/hepatologists, whereas general practitioners, surgeons, and physicians tended to diagnose cirrhosis incidentally (P < 0.001). The majority of patients diagnosed incidentally (n = 48/66, 73%) had previous thrombocytopenia, splenomegaly, or high noninvasive fibrosis scores. Following diagnosis, patients diagnosed incidentally were less likely to undergo HCC screening. Conclusion: The majority of patients with NAFLD cirrhosis are diagnosed incidentally. These patients are more likely to have advanced liver disease and HCC. Increased awareness of screening for cirrhosis is needed in patients with NAFLD. (Hepatology Communications 2017;1:53-60).

Complex non-invasive fibrosis models are more accurate than simple models in non-alcoholic fatty liver disease.

BACKGROUND AND AIM: Significant hepatic fibrosis is prognostic of liver morbidity and mortality in non-alcoholic fatty liver disease (NAFLD); however, it remains unclear whether non-invasive fibrosis models can determine this end-point. We therefore compared the accuracy of simple bedside versus complex fibrosis models across a range of fibrosis in a multi-centre NAFLD cohort. METHODS: Simple (APRI, BARD) and complex (Hepascore, Fibrotest, FIB4) fibrosis models were calculated in 242 NAFLD subjects undergoing liver biopsy. Significant (F2-4) and advanced fibrosis (F3,4) were defined using Kleiner criteria. Models were compared using area under the receiver operator characteristic curves (AUC). Cut-offs were determined by Youden Index or 90% predictive values. RESULTS: For significant fibrosis, non-invasive fibrosis models had modest accuracy (AUC 0.707-0.743) with BARD being least accurate (AUC 0.609, P < 0.05 vs others). Using single cut-offs, sensitivities and predictive values were < 80%; using two cut-offs, > 75% of subjects fell within indeterminate ranges. Simple models had significantly more subjects within indeterminate ranges than complex models (99.1-100% vs 82.1-84.4% respectively, P < 0.05 for all). For advanced fibrosis, complex models were more accurate than BARD (AUC 0.802-0.858 vs 0.701, P < 0.05). Using two cut-offs, complex models had fewer individuals within indeterminate ranges than BARD (11.1-32.3% vs 70.7%, P < 0.01 for all). For cirrhosis, complex models had higher AUC values than simple models. CONCLUSIONS: In NAFLD subjects, non-invasive models have modest accuracy for determining significant fibrosis and have predictive values less than 90% in the majority of subjects. Complex models are more accurate than simple bedside models across a range of fibrosis.