Research ArticleA systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver
Introduction
Patients with NAFLD are increasingly seen in hepatology clinics, and their management requires decisions on invasive exploration, follow-up, and treatment. These decisions are based on our understanding of the natural history of this disease, which has so far been largely incomplete. One reason is the inter-individual variability in the natural course of the disease, a feature shared by many other chronic liver diseases. Another reason is the significant heterogeneity of the clinical presentation. Indeed, NAFLD encompasses both steatohepatitis (NASH), considered the more aggressive form of the disease, and NAFL (non-alcoholic fatty liver) grouping isolated steatosis and steatosis with mild lobular inflammation alone [1], [2]. NAFL is thought of as a benign, non-progressive condition which does not increase overall or liver-related mortality [3], [4], [5]. In contrast, patients with NASH have a ten-fold increase in liver-related mortality, die of cirrhosis, and develop liver cancer [3], [6], [7], [8], [9].
Because of this clear-cut dichotomy, NAFL and NASH appear to be very distinct entities, somehow diverging in the early course of the disease. This paradigm was corroborated by experimental data suggesting that in animal models, triglyceride storage protects liver cells from fatty acid-induced apoptotic pathways [10]; moreover, blocking the final step of triglyceride synthesis by genetic inactivation of diacylglycerol acyltransferase type 2 results in less steatosis, but more inflammation, oxidative stress, and fibrosis [11]. Therefore, the current thinking is that triglycerides are a form of safe storage of liver fat and therefore patients with steatosis alone are protected from hepatic deterioration. In this case, there should be little or no transition from steatosis to steatohepatitis, or at least no more than expected from the background noise due to sampling variability of the liver biopsy.
We undertook a study of NAFLD patients with repeat liver biopsies in order to better understand the histological course of the disease, specifically in relation to the initial findings of NAFL or steatohepatitis. We also aimed at correlating histological changes to changes in the metabolic co-morbidities often associated with NAFLD. Only patients that were unable to successfully implement lifestyle modifications and thus had persistent NAFLD were included.
Section snippets
Patients and methods
We retrospectively analyzed our histology database between 1998 and 2009 and identified all adult patients diagnosed with primary NAFLD (defined as steatosis ⩾10%) who had undergone a repeat liver biopsy one year or more after the index biopsy. Patients with liver diseases other than NAFLD (drug-induced hepatotoxicity, chronic hepatitis B or C, genetic hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, α1-antitrypsin deficiency, Wilson’s disease,
Study population and overall changes between biopsies
Of the 109 patients fulfilling the inclusion criteria, 32 had been treated with an active drug in a randomized controlled trial and 7 had incomplete clinical or biological data. Therefore, 70 patients were analyzed (Table 1 and Fig. 1). Nine patients had isolated, bland steatosis (without any ballooning or lobular inflammation), and 16 patients had steatosis and minimal lobular inflammation, without ballooning or advanced fibrosis. Thus 25 patients had insufficient criteria for NASH and
Discussion
These findings challenge the current dogma that NAFL is a non-progressive condition that rarely, if ever, results in NASH or advanced fibrosis. The dichotomy between NASH, a potentially progressive condition, and NAFL (i.e., steatosis alone or with mild inflammation) that is not associated with adverse hepatic outcomes, has until now been the basis of our understanding of the natural history of NAFLD. Early studies on a small number of patients with repeat liver biopsies failed to show any
Financial support
The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n° HEALTH-F2-2009-241762 for the project FLIP.
Conflict of interest
VR is a consultant for Abbot, Conatus, Galmed, Genfit, Gilead, Enterome, and Phenex all unrelated to the present manuscript.
Acknowledgments
Members of the LIDO Study Group are: André Grimaldi, Philippe Giral, Eric Bruckert, Arnaud Basdevant, Karine Clement, Agnès Hartemann-Heurtier, Fabrizio Andreelli, Sophie Gombert, Sophie Jacqueminet, Dominique Simon, Joseph Moussalli, Pascal Lebray, Dominique Bonnefont-Rousselot, Yves Benhamou, Cecilia D’Arrondel, Carole Bernhardt, Isabelle Ravalet, Hôpital Pitié-Salpêtrière; Philippe Podevin, Hôpital de Provins; Christian Boitard, Etienne Larger, Agnès Sola Hôpital Hotel-Dieu; Lawrence
References (22)
- et al.
The natural history of non-alcoholic fatty liver disease: a population-based cohort study
Gastroenterology
(2005) - et al.
The natural history of non-alcoholic fatty liver: a follow-up study
Hepatology
(1995) - et al.
Non-alcoholic fatty liver disease: a spectrum of clinical and pathological severity
Gastroenterology
(1999) - et al.
Non-alcoholic fatty liver, steatohepatitis, and the metabolic syndrome
Hepatology
(2003) - et al.
A position paper on NAFLD/NASH based on the EASL 2009 Special Conference
J Hepatol
(2010) - et al.
Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis
J Hepatol
(2009) - et al.
Non-alcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research
Semin Liver Dis
(2012) - et al.
The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association
Hepatology
(2012) - et al.
Long-term follow-up of patients with NAFLD and elevated liver enzymes
Hepatology
(2006) - et al.
Long term prognosis of fatty liver: risk of chronic liver disease and death
Gut
(2004)
Final results of a long-term, clinical follow-up in fatty liver patients
Scand J Gastroenterol
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Members of the LIDO (Liver Injury in Diabetes and Obesity) Study Group are listed in the Acknowledgments section.