Diabetes mellitus

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Postgrad Med J 2006;82:315-322 doi:10.1136/pgmj.2005.042200
* Review
Treatment of non-alcoholic fatty liver disease
1. L A Adams1, 
2. P Angulo2
+Author Affiliations
1. 1School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Perth, Australia
2. 2Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, USA1. Correspondence to:
 Dr P Angulo
 Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA;angulohernandez.paul@mayo.edu
* Received 9 October 2005
* Accepted 3 December 2005
Abstract
Non-alcoholic fatty liver disease (NAFLD) is common and may progress to cirrhosis and its complications. The pathogenesis of steatosisand cellular injury is thought to be related mostly to insulin resistance and oxidative stress. Therefore, management entails identification and treatment of metabolic risk factors, improving insulin sensitivity, and increasing antioxidant defences in the liver. Weight loss and exercise improve insulin sensitivity. Bariatric surgery may improve liver histology in patients with morbid obesity.Insulin sensitising drugs showed promise in pilot trials as have a number of hepatoprotective agents. Further randomised, well controlled trials are required to determine the efficacy of these drugs.
Non-alcoholic fatty liver disease (NAFLD) occurs across all age groups and ethnicities and is recognised to occur in 14%–30% of the general population.1,2 Primary NAFLD is related to insulin resistance andthus frequently occurs as part of the metabolic changes that accompany obesity, diabetes, and hyperlipidaemia. However, it is important to exclude secondary causes of hepatic steatosis (table 1) by clinical assessment. Treatment of these conditions differs and revolves around correcting the underlying cause.3
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Table 1
 Causes of non-alcoholic fatty liver disease
PATHOGENESIS
The pathogenesis of NAFLD is not fully understood, however the finding that not all patients with steatosis develop hepatic inflammation and hepatocellular damage has led to the hypothesis that different pathogenic factors lead firstly to hepaticsteatosis and secondly to hepatic damage (“the second hit”).4 Accumulation of hepatic fat is closely linked to insulin resistance, which increases lipolysis of peripheral adipose tissue with resultant increased fat influx into the liver in the form of free fatty acids. Furthermore, insulin resistance promotes de novo triglyceride synthesis within the liver and inhibits fatty acid oxidation therebypromoting triglyceride accumulation.5 Therefore, improving insulin sensitivity has been a key strategy in the treatment of NAFLD.
It is unknown what “second hit” leads to the development of liver damage, although several factors have been implicated including oxidative stress, mitochondrial abnormalities, and hormonal disturbances involving leptin and adiponectin.6 In particular, oxidative stresswith subsequent lipid peroxidation and generation of reactive oxygen species seems to be prominent in NAFLD and has been identified as a therapeutic target for antioxidants. Injury by secondary insults leads to the generation of pro-inflammatory cytokines such as tumour necrosis factor α, which are targeted by hepatoprotective agents such as pentoxifylline. Hyperinsulinaemia and hyperglycaemia mayalso upregulate pro-fibrogenic cytokines and thus provide a rational for insulin sensitising agents such as metformin and the thiozoladinediones to prevent progressive liver damage.7
NATURAL HISTORY
NAFLD exists as a histological spectrum of changes; simple steatosis refers to >5% hepatic steatosis in the absence of significant inflammation and hepatocellular damage whereas non-alcoholic...
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