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‘You’ll never find what you’re not looking for’: NASH – under-diagnosed and under-treated

17th December 2020

NAFLD (non-alcoholic fatty liver disease) is increasingly in the spotlight due to its high prevalence and growing incidence in people across the world. As obesity and diabetes pandemics gather pace, cases of NAFLD are only going one way, so the research world is throwing its weight behind the hunt for better diagnostic tools and effective treatments.

A valuable update on these efforts was provided by Dr Kenneth Cusi at this month’s 18th World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease (WCIRDC). In his presentation, Dr Cusi, who is Professor of Medicine and Chief of the Division of Endocrinology, Diabetes and Metabolism at the University of Florida, compared NAFLD and diabetes to a bad marriage – diabetes exacerbates NAFLD, increasing the risk of non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma, while NAFLD makes diabetes harder to control and insulin resistance worse. To turn this toxic relationship round, he called for NASH to be integrated into a ‘triangle of care’ with cardiovascular disease (CVD) and kidney disease when it comes to cardiometabolic risk reduction; the pharmaceuticals used for treating the liver can benefit the other two, and vice versa.

The thrust of his presentation was that NASH is being missed in clinics, with the result that many patients only see a hepatologist once they already have end-stage organ damage. For endocrinologists who say they don’t see NASH or cirrhosis in clinic, he says that you’ll never find what you’re not looking for and that it’s being missed in the same way that nephropathy was before clinicians started measuring albumin in urine.

Dr Cusi is part of a consortium called TARGET-NASH, which has gathered data on over 3000 patients from 40 centres across the US – 1440 with cirrhosis and 1645 with NASH without cirrhosis. Of those with cirrhosis, 72% had diabetes. And having diabetes almost tripled the odds of having end-stage liver disease.

As one of the reasons it’s being missed, Dr Cusi highlighted a study just accepted into Diabetes Care: out of 561 patients with type 2 diabetes, 70% had fat in the liver, 21% had fibrosis, but only 10% showed elevated liver enzymes, so this is not all that should be looked for in clinic.

He also highlighted the extra-hepatic risks of fatty liver. If you have fatty liver and you don’t have diabetes, you have a two- to threefold higher risk of developing type 2 diabetes. There is also a strong link to cardiovascular disease.

How, then, to identify the patients who need to see a hepatologist? For Dr Cusi, looking for fibrosis is the key. This can be done with a simple Fibrosis-4 (FIB-4) diagnostic panel, which costs nothing and is done using a scoring system from the parameters of age, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and platelet count. If the result falls into either indeterminate or high, then elastography imaging, using a device such as a Fibroscan, can measure liver stiffness and tell you if a patient is at higher risk of cirrhosis and requires treatment.

Finally, he moved on to treatment of NASH using medication. First up was pioglitazone – in some patients, it reduces inflammation in NASH and prevents fibrosis progression, and can result in resolution, leaving them with minimal or no inflammation.

For clinicians concerned about weight gain, he pointed out that the weight gain from pioglitazone has nothing in common with weight gain from excess caloric intake. With the drug, insulin resistance is improved and the patient gets the benefits that go hand in hand with that, such as reduced visceral fat and hyperglycaemia. It also lowers risk of cardiovascular disease and improves myocardial function, all of which worsen from weight gain caused by eating too many calories.

Citing four controlled studies, Dr Cusi said that starting with lower doses can also help to prevent the weight gain. Alternatives include combining with injectable GLP-1 receptor agonists (liraglutide being the most studied), oral semaglutide or an SGLT-2 inhibitor. 

He concluded that to save more patients from the progression of NASH and end-stage organ damage, it needs to become part of the cardiovascular disease and nephropathy club, making the third point of the treatment triangle.

Coming soon…

New EASD e-Learning courses on insulin resistance and on NAFLD are currently in development and will be launching in 2021.

For more on NAFLD and NASH, see module 2 in our GLP-1 receptor agonist course, GLP-1 and obesity, NAFLD and NASH.

The opinions expressed in this blog are those of the author, Dr Eleanor D Kennedy.

Sessions at the 18th World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease (WCIRDCD) are now available online at