Elsevier

Journal of Hepatology

Volume 59, Issue 3, September 2013, Pages 550-556
Journal of Hepatology

Research Article
A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver

https://doi.org/10.1016/j.jhep.2013.04.027Get rights and content

Background & Aims

Disease progression in non-alcoholic fatty liver disease (NAFLD) is not well understood and there is controversy about whether non-alcoholic fatty liver (NAFL, i.e., steatosis alone or with mild inflammation not qualifying for steatohepatitis) can evolve towards steatohepatitis (NASH) with fibrosis.

Methods

We reviewed 70 patients with untreated NAFLD and with two biopsies performed more than one year apart. Clinical and biological data were recorded at the time of both biopsies. Alcohol consumption did not change during follow-up.

Results

Initially 25 patients had NAFL and 45 had NASH and/or advanced fibrosis. After a mean follow-up of 3.7 years (s.d. 2.1), 16 NAFL patients developed NASH, eight with severe ballooning and six with bridging fibrosis on the follow-up biopsy. Patients with mild lobular inflammation or any degree of fibrosis were at higher risk of progression than those with steatosis alone. Those with unambiguous disease progression were older and had worsening of their metabolic risk factors (higher weight and more diabetes at baseline and during follow-up). In the whole cohort, ballooning progression and bridging fibrosis often occurred together and co-existed with a reduction in ALT, higher weight gain, and a higher incidence of diabetes during follow-up.

Conclusions

A substantial proportion of patients with NAFL can progress towards well-defined NASH with bridging fibrosis, especially if metabolic risk factors deteriorate. Even mild inflammation or fibrosis could substantially increase the risk of progression when compared to steatosis alone. Current monitoring practices of these patients should be revised.

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)

  • S. Dam-Larsen et al.

    Final results of a long-term, clinical follow-up in fatty liver patients

    Scand J Gastroenterol

    (2009)
  • Cited by (392)

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    Members of the LIDO (Liver Injury in Diabetes and Obesity) Study Group are listed in the Acknowledgments section.

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