“A vicious spiral of two worsening diseases”: NAFLD and type 2 diabetes

Look to the liver – for non-alcoholic fatty liver disease (NAFLD) has important links with type 2 diabetes and metabolic syndrome, and can worsen the risk of cardiovascular disease.

NAFLD is a multisystem disease that begins with fat accumulation in the liver. Once 5% or more of the liver cells contain fat, the person actually has NAFLD and they are looking at a serious health issue that is attracting increasing attention among healthcare professionals. According to Professor Chris Byrne, Southampton University, speaking at this year’s Advanced Technologies and Treatment for Diabetes meeting, NAFLD may progress to liver fibrosis, cirrhosis and liver cancer. It is also associated with an increased risk of chronic kidney disease, cardiovascular disease and type 2 diabetes. And, importantly, it is often found together with metabolic syndrome, which may provide a route into earlier diagnosis of NAFLD during routine checks; maybe something can be done before it progresses too far.

Links with type 2 diabetes

Professor Byrne describes NAFLD and type 2 diabetes as a “vicious spiral of worsening disease.” Over the last few years, she and others have published evidence that NAFLD increases the risk of type 2 diabetes more than two-fold, and the presence of type 2 diabetes then accelerates the rate of progression of NAFLD to liver fibrosis and maybe even hepatocellular carcinoma. Hence, a vicious spiral. Worse still, NAFLD also doubles the risk of cardiovascular disease and increases the risk of chronic kidney disease by 50%.

Here is some of that evidence. A meta-analysis published in 2018 and updated in 2020, covering half a million patients, showed that the presence of NAFLD doubled the risk of type 2 diabetes. This increased risk is likely driven by marked hepatic insulin resistance and increased hepatic glucose output in NAFLD.

Another study, involving paired liver biopsies separated by six years, showed that 56% of patients with type 2 diabetes and NAFLD progressed to liver fibrosis, compared with 21% of those with NAFLD but no diabetes.  This was confirmed by research based on European registry data covering 18 million individuals and showing that a history of diabetes at baseline was the strongest independent predictor of a diagnosis of cirrhosis or liver cancer.

NAFLD and cardiovascular risk

“Those people who are cynical about NAFLD being an independent risk factor for cardiovascular disease in patients who have already developed type 2 diabetes often say to me ‘well, there is co-existing type 2 diabetes in these individuals and that’s what’s driving the cardiovascular disease risk’,” said Professor Byrne. So, she addressed this question with Sarah Wild at Edinburgh University, drawing upon Scottish Diabetes Registry data, with its cohort of over 134,000 individuals. They were able to compare cardiovascular events in those with liver disease and diabetes and those with diabetes alone. This clearly showed that NAFLD is an independent risk factor for incident or recurrent cardiovascular disease (CVD).

Professor Byrne believes the link with cardiovascular disease comes from the atherogenic dyslipidaemia, involving very low-density lipoprotein particles, that occurs in the context of metabolic syndrome. “The actual mechanisms involved are very complicated and seem to involve the release of proinflammatory and prothrombotic factors as well.”

Once NAFLD has been diagnosed, the diabetes team should be very aware of the increased risk of CVD. Prof Byrne recommends using your local cardiovascular risk tool, and then doubling the score for the presence of NAFLD.  

Diagnosing NAFLD

So, hopefully, with raised awareness NAFLD will be spotted earlier and more often by both non-specialists and diabetologists. Professor Byrne thinks that, ideally, all patients with type 2 diabetes should be screened for the condition. Raised liver enzymes can be a sign, of course. And there are five easily measured features of metabolic syndrome that should set alarm bells ringing during routine tests – high blood pressure, increased triglycerides, low HDL, large waist circumference and glucose of 6 mmol/l or more. There’s usually insulin resistance and high fasting insulin too, and the above-mentioned atherogenic dyslipidaemia – so plenty to look out for.

At present, liver enzymes and metabolic syndrome markers are the mainstay of diagnosis of NAFLD and data can be fed into the established diagnostic tools ELF and FIB-4 to get a score. But what threshold score should be used to warrant further investigation by elastography – also known as Fibroscan – which assesses the degree of liver fibrosis?  “This is work in progress,” said Professor Byrne. “NICE recommends an ELF threshold of 10.5 to identify those with F3 and F4 fibrosis, but the lower grade F2 should not be ignored, so we go down to a threshold of 9. Then we find that hepatology can’t cope with all these referrals for elastography investigation, so we’ve adopted a threshold of around 10. Choose your thresholds in terms of what your local service can handle.” She added that she’s expecting elastography to find its way into more diabetes clinics in the not too distant future, which will make accurate diagnosis of NAFLD easier.

Treating – and preventing – NAFLD

So what about treatment? It’s so important to consider that cardiovascular risk. “Pioglitazone, which was licensed 20 years ago, has become the forgotten cost-effective and cardioprotective drug for type 2 diabetes,” said Professor Byrne. The good news is that randomised clinical trials have shown that pioglitazone has proven efficacy in resolving NAFLD in at least 50% of patients and it also has a well-established cardioprotective effect. Similar benefits can be had from the GLP-1 receptor agonists, with the added benefit of weight loss.  “The GLP-1 receptor agonists are going to become very popular in type 2 diabetes,” she added.  And weight loss, through diet and/or medication, is very effective at facilitating loss of liver fat (as Diabetes UK’s DiRECT trials have shown) so may help stop progression of NAFLD or even prevent it from developing in the first place.

So, there’s yet another reason to encourage weight loss in type 2 diabetes management: prevent NAFLD and you prevent so many other problems down the line.

For more on this topic enrol on our course ‘Non-alcoholic fatty liver disease’, written and presented by Professor Michael Roden.

Watch out for our forthcoming debate on screening for NAFLD between Professors Gianluca Perseghin and Ken Cusi, part of our series ‘The long and the short of it’.

The views expressed in this article are those of the author, Dr Eleanor D Kennedy.