T. Hardy

Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: Implications for prognosis and clinical management

BACKGROUND AND AIMSnThere remains uncertainty about the natural history of non-alcoholic fatty liver disease (NAFLD). The spectrum of NAFLD includes non-alcoholic fatty liver (NAFL; steatosis without hepatocellular injury) and steatohepatitis (NASH; steatosis with hepatocyte ballooning degeneration±fibrosis). Our aim was to assess the histological severity of NAFLD in a cohort with serial biopsy data, and determine factors predicting progression.nnnMETHODSnPatients with two liver biopsies more than a year apart were identified. Clinical and laboratory data were collected from the time of liver biopsy.nnnRESULTSn108 patients had serial biopsies (median interval 6.6years, range 1.3-22.6). 81 (75%) patients had NASH and 27 had NAFL. Overall, 45 (42%) patients had fibrosis progression, 43 (40%) had no change in fibrosis, while 20 (18%) had fibrosis regression. Importantly, no significant difference in the proportion exhibiting fibrosis progression was found between those with NAFL or NASH at index biopsy (37% vs. 43%, p=0.65). Progression to NASH was seen in 44% of patients with baseline NAFL. Of 10 patients with NAFL who had fibrosis progression, 3 progressed by 1 stage, 5 by 2 stages and 2 by 3 stages; all had NASH on follow-up biopsy. Of concern, 6 of 27 (22%) patients with baseline NAFL, reached stage 3 fibrosis at follow-up biopsy. Among the patients with NAFL, 80% of those having fibrosis progression were diabetic at the follow-up liver biopsy compared with 25% of non-progressors (p=0.005).nnnCONCLUSIONSnContrary to current dogma, this study suggests that steatosis can progress to NASH and clinically significant fibrosis.

Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis

OBJECTIVES:Non-invasive fibrosis scores are widely used to identify/exclude advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). However, these scores were principally developed and validated in patients aged between 35 and 65 years of age. The objective of this study was to assess the effect of age on the performance of non-invasive fibrosis tests in NAFLD.METHODS:Patients were recruited from European specialist hepatology clinics. The cohort was divided into five age-based groups: ≤35 (n=74), 36–45 (n=96), 46–55 (n=197), 56–64 (n=191), and ≥65 years (n=76), and the performance of the aspartate aminotransferase (AST)/alanine transaminase (ALT) ratio, fibrosis 4 (FIB-4), and NAFLD fibrosis score (NFS) for advanced fibrosis (stage F3–F4) for each group was assessed using liver biopsy as the standard.RESULTS:Six hundred and thirty-four patients were included. The diagnostic accuracy of the AST/ALT ratio was lower than NFS and FIB-4 in all the age groups. The AST/ALT ratio, NFS, and FIB-4 score performed poorly for a diagnosis of advanced fibrosis in those aged ≤35 years (area under the receiver operating characteristic curves (AUROCs 0.52, 0.52, and 0.60, respectively). For all groups >35 years, AUROCs for advanced fibrosis were similar for the NFS and FIB-4 score (range 0.77–0.84). However, the specificity for advanced fibrosis using the FIB-4 and NFS declined with age, becoming unacceptably low in those aged ≥65 years (35% for FIB-4 and 20% for NFS). New cutoffs were derived (and validated) for those aged ≥65 years, which improved specificity to 70% without adversely affecting sensitivity (FIB-4 2.0, sensitivity 77%; NFS 0.12, sensitivity 80%).CONCLUSIONS:The NFS and FIB-4 scores have similar accuracy for advanced fibrosis in patients aged >35 years. However, the specificity for advanced fibrosis is unacceptably low in patients aged ≥65 years, resulting in a high false positive rate. New thresholds for use in patients aged ≥65 years are proposed to address this issue.

Further delineation of fibrosis progression in NAFLD: evidence from a large cohort of patients with sequential biopsies

Further delineation of fibrosis progression in NAFLD: evidence from a large cohort of patients with sequential biopsies Stuart Mcpherson* 1, Raluca Pais2, Luca Valenti3, Joern M. Schattenberg4, Jean-Francois Dufour5, Emmanuel Tsochatzis6 , Sven Francque7, Timothy Hardy1, Marie Boyle1, Dina Tiniakos1, Vlad Ratziu2, Quentin Anstee1 and EPOS and European NAFLD registry 1Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom, 2Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France, 3University of Milan, Milan, Italy, 4Department of Medicine, University Hospital, Mainz, Germany, 5University of Bern, Bern, Switzerland, 6UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, United Kingdom, 7University of Antwerp, Antwerp, Belgium

Editorial: NAFLD in Asia—clinical associations with advanced disease become clearer

though multiple studies have attributed lower rates of treatment with immune suppression and anti-TNF agents in older adults to provider preference, no studies have formally evaluated this topic. Finally, if a major goal in stratifying IBD patients by age is better prediction of clinical outcomes, chronological age on its own in a heterogeneous ageing IBD population may be a less effective tool than a measure of global function. Compared to patient age and comorbidities, clinical frailty syndrome, a measure of reserve and function across multiple physiologic systems, better predicts chemotherapy outcomes, colonoscopy outcomes (Taleban et al, submitted) and poor perioperative IBD outcomes. Patient age and comorbidity do not wholly account for poor outcomes and thus their clinical utility to risk-stratify older patients is limited. It is time to incorporate tools beyond age or comorbidity alone to predict IBD outcomes.

P615 DIFFERENTIAL DNA METHYLATION OF GENES INVOLVED IN FIBROSIS PROGRESSION IN NAFLD AND ALD

Background and Aims: Fibrosis is determined by genetic and exogenous factors. We observed that administration of carbon tetrachloride (CCl4) induces fibrosis in liver and heart. To dissect common and organ-specific mechanisms of fibrosis, we employed BXD recombinant inbred lines as a genetic reference population (GRP). Our aim was to identify potential candidate genes for hepatic and cardiac fibrogenesis. Methods: Thirty BXD lines were used as GRP for quantitative trait loci (QTL)-analyses. Fibrosis was induced by CCl4 (1.4mg/kg/week, 12 i.p. injections). Coinciding liver and heart loci linked to collagen accumulation were screened for locally regulated genes (cisQTGs) by expression QTL (eQTL)-analysis, availing of transcriptomic data of CCl4-treated BXD lines. In-silico analyses affirmed Rafkinase inhibitor 1 (Rkip1) as a potential candidate gene. Hence, we compared collagen accumulation in CCl4-challenged Rkip1knockout (Rkip) and wild-type mice after Sirius red staining of liver and heart sections. Results: We observed significant differences for hepatic and cardiac fibrosis among the BXD lines. These were conferred by common QTLs as well as organ-specific QTLs on chromosomes 4, 5, and 18. Rkip1 was identified as major cis-QTG (LRS = 64.6). CCl4-challenged Rkip mice showed significant (p < 0.05) less cardiac collagen accumulation, whereas no differences were observed in liver. Conclusions: This study reveals that CCl4-induced fibrosis is a systemic model allowing comparative analysis of fibrosis in liver and heart. QTL-analysis of hepatic and cardiac fibrosis identified common and organ-specific QTLs of fibrogenesis. Rkip1 deficiency has anti-fibrotic effects in heart, but not in liver pointing to organspecific mechanisms of fibrosis progression in this model.

PTH-090 Natural History Of Nafld: A Study Of 108 Patients With Paired Liver Biopsies

Introduction Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in many countries. There remains considerable uncertainty about natural history and prognosis. Few studies, totalling <400 patients, have examined the evolution of steatosis/steatohepatitis and fibrosis of NAFLD in patients with paired biopsies. In general it is thought that fibrosis progression in patients with “NAFL” (steatosis +/- mild inflammation) is uncommon, whereas non-alcoholic steatohepatitis (NASH; steatosis + hepatocyte ballooning and inflammation) more frequently progresses. Our aim was to assess the histological severity of NAFLD in a cohort with serial liver biopsy data and to determine clinical factors that predict fibrosis progression. Methods Patients with 2 liver biopsies >1 year apart were identified from the Newcastle Hospitals NAFLD clinic. Clinical and laboratory data were collected from the time of liver biopsy. Results 108 patients (mean age 48 ± 12 years; 66% male; 48% diabetic) were identified with ≥2 liver biopsies (median interval 6.6 years, range 1.3–22.6). 81 (75%) patients had NASH and 27 patients with NAFL. Overall 45 (42%) patients had progression of fibrosis, 43 (40%) had no change in fibrosis, while 20 (18%) had fibrosis regression. The mean rate of fibrosis was 0.08 ± 0.25 stages/year overall, increasing to 0.29 ± 0.24 stages/year in progressors. Importantly, no significant difference in the proportion exhibiting fibrosis progression was found between those with NAFL or NASH at index biopsy (10/27 (37%) vs. 36/83 (43%) p = 0.65). 12/27 (44%) with NAFL at baseline progressed to NASH at follow-up biopsy, whereas 6/75 (8%) with NASH regressed to NAFL. Weight change was a significant factor associated with inter-biopsy change in disease activity measured by NAFLD activity score (rs,=0.23 p = 0.026). Of 10 patients with NAFL who had fibrosis progression, 3 progressed by 1 stage, 5 by 2 stages and 2 by 3 stages; all had NASH on the follow-up biopsy. Of concern, 6 of 27 (22%) patients with baseline NAFL had reached stage 3 fibrosis at the follow up biopsy, but none were cirrhotic. Among the patients with NAFL, 80% of those who had fibrosis progression were diabetic at the time of follow-up liver biopsy compared with 25% of non-progressors (p = 0.005). The FIB-4 score was the only significant baseline factor that predicted fibrosis progression (OR 2.1 [95% CI: 1.1–3.9], p = 0.02). However, the AUROC was only 0.63 (p = 0.04). Conclusion Contrary to current dogma, this study suggests that NAFL is not entirely benign and has the potential to progress to NASH and clinically significant fibrosis, particularly if patients develop diabetes. Disclosure of Interest None Declared.