Non-invasive method predicts severity of liver disease

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Using information collected in a liver biopsy study, researchers at Cardiff University have developed a method of determining the onset of non-alcoholic steatohepatitis (NASH) through the analysis of lipids, metabolites and clinical markers in blood.

NASH is the most extreme form of non-alcoholic fatty liver disease (NAFLD) – a range of conditions caused by a build-up of fat in the liver. With NASH, inflammation of the liver damages the cells, potentially causing scarring and cirrhosis.

Currently, the diagnosis of NASH can only be done with a liver biopsy – an invasive and costly procedure. The new research could lead to a simple blood test that could catch the
onset of NASH before inflammation damages the liver.

Dr You Zhou from Cardiff University’s Systems Immunity Research Institute said: “Many people with non-alcoholic steatohepatitis do not have symptoms and are not aware they are developing a serious liver problem. As such, diagnosis often comes after irreversible damage is done. Our quicker and less invasive method of diagnosis could mean that more people with non-alcoholic fatty liver disease could be easily tested to determine whether they are progressing to non-alcoholic steatohepatitis, the more severe form of the disease.”

A healthy liver should contain little or no fat. It’s estimated that around 20% of people in the UK have early stages of NAFLD where there are small amounts of fat in their liver. NASH is estimated to affect up to 5% of the UK population and is now considered to be one of the main causes of cirrhosis – a condition where irregular bumps replace the smooth liver tissue, making it harder and decreasing the amount of healthy cells to support normal functions. This can lead to complete liver failure.

Common risk factors for both NAFLD and NASH are obesity, lack of physical exercise and insulin resistance. But if detected and managed at an early stage, it’s possible to stop both NAFLD and NASH from getting worse.

The new method of NASH diagnosis will undergo further investigation with a view to developing a simple blood test that can be used by clinicians to provide effective medical care for patients at high risk of the disease.

Abstract
Background & Aims: Use of targeted mass spectrometry (MS)-based methods is increasing in clinical chemistry laboratories. We investigate whether MS-based profiling of plasma improves noninvasive risk estimates of nonalcoholic steatohepatitis (NASH) compared with routinely available clinical parameters and patatin-like phospholipase domain-containing protein 3 (PNPLA3) genotype at rs738409.
Methods: We used MS-based analytic platforms to measure levels of lipids and metabolites in blood samples from 318 subjects who underwent a liver biopsy because of suspected NASH. The subjects were divided randomly into estimation (n = 223) and validation (n = 95) groups to build and validate the model. Gibbs sampling and stepwise logistic regression, which fulfilled the Bayesian information criterion, were used for variable selection and modeling.
Results: Features of the metabolic syndrome and the variant in PNPLA3 encoding I148M were significantly more common among subjects with than without NASH. We developed a model to identify subjects with NASH based on clinical data and PNPLA3 genotype (NASH Clin Score), which included aspartate aminotransferase (AST), fasting insulin, and PNPLA3 genotype. This model identified subjects with NASH with an area under the receiver operating characteristic of 0.778 (95% confidence interval, 0.709–0.846). We then used backward stepwise logistic regression analyses of variables from the NASH Clin Score and MS-based factors associated with NASH to develop the NASH ClinLipMet Score. This included glutamate, isoleucine, glycine, lysophosphatidylcholine 16:0, phosphoethanolamine 40:6, AST, and fasting insulin, along with PNPLA3 genotype. It identified patients with NASH with an area under the receiver operating characteristic of 0.866 (95% confidence interval, 0.820–0.913). The NASH ClinLipMet score identified patients with NASH with significantly higher accuracy than the NASH Clin Score or MS-based profiling alone.
Conclusions: A score based on MS (glutamate, isoleucine, glycine, lysophosphatidylcholine 16:0, phosphoethanolamine 40:6) and knowledge of AST, fasting insulin, and PNPLA3 genotype is significantly better than a score based on clinical or metabolic profiles alone in determining the risk of NASH.

Authors
You Zhou, Matej Orešič, Marja Leivonen, Peddinti Gopalacharyulu, Jenni Hyysalo, Johanna Arola, An Verrijken, Sven Francque, Luc Van Gaal, Tuulia Hyötyläinen, Hannele Yki-Järvinen.

Cardiff University material
Clinical Gastroenterology and Hepatology abstract


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