Prevalence of NASH in people with obesity

The prevalence of both obesity and NAFLD is increasing; there is a high coincidence of the conditions and both are set to become major health challenges in the coming years.1,2 Individuals with obesity, type 2 diabetes mellitus (T2DM), dyslipidaemia and insulin resistance are at greatest risk of developing NAFLD.3 Importantly, it is estimated that 37% of people with NAFLD are obese, whereas 90% of severely obese people also have NAFLD.1

In Europe and the United States, the increase in prevalence of obesity roughly mirrors the increase in the prevalence of NAFLD. In the US, it is estimated that around one-third of the population are obese, and approximately 30% are likely to have NAFLD.2 Data from two studies found that in people with obesity the prevalence of NAFLD was 76% and 93%, of which, progression to NASH was 37% and 26%, respectively.4,5 Furthermore, degree of obesity has been linked to the incidence of NASH; following death apparently unrelated to NAFLD, autopsy revealed that 19% of morbidly obese people had undiagnosed NASH whereas this figure was just 3% in non-obese people.6

Individuals with obesity, type 2 diabetes mellitus (T2DM), dyslipidaemia and insulin resistance are at greatest risk of developing NAFLD.3 Importantly, it is estimated that 37% of people with NAFLD are obese, whereas 90% of severely obese people also have NAFLD.1

Compounding factors

Obesity is a strong predictor for the development of NAFLD; this association is influenced by both genetic predisposition and lifestyle choices, and progression of NAFLD is likely dependent on a number of factors.7–12

Genetic factors

Studies have revealed a range of genetic risk factors which can increase the deposition of fat in the liver and accelerate the onset of fibrosis. Two examples are listed below:

  • Patatin­like phospholipase domain­containing 3 (PNPLA3): Liver fat content is markedly increased (14.2%) in people with obesity homozygous for the PNPLA3 “MM” variant, but not in those with the “II” variant (4.7%), and neither variant has been shown to correlate with body mass index (BMI).7,8
  • Transmembrane 6 superfamily member 2 (TM6SS2): People with obesity who possess the minor variant of the NAFLD-associated TM6SS2 gene are significantly more likely to have liver fibrosis than those carrying the common variant (p=0.04).9

Lifestyle factors

Fructose consumption is linked to the development of obesity and is an identified risk factor for NAFLD.10,11 A large cross-sectional analysis found that consumption of high fructose food and drinks is associated with increased incidence and severity of liver injury and consequent fibrosis.12

Fibrosis

NAFLD and NASH are associated with severe comorbidities which may be further complicated by obesity and obesity-related factors.13,14

Obesity is associated with increased levels of circulating leptin,15 which has a direct effect on hepatic cells. It has been suggested that this may play a role in the progression of liver fibrosis in NASH, which is associated with complications such as cirrhosis, eventual liver failure and hepatocellular carcinoma (HCC).16,17 However, the role of increased obesity-associated leptin in the development of fibrosis has yet to be confirmed and studies are ongoing.16

The majority of people with obesity and NASH-related HCC have advanced fibrosis (F3 and F4; 88%), while the remainder have early fibrosis (F1 and F2; 12%).13 With increasing prevalence of obesity and its strong association with NASH, advanced fibrosis due to NASH is predicted to become the most common cause of HCC in developed countries.18

Assessment and diagnosis

Due to high rates of NASH in people with obesity, regular monitoring and assessment for NASH is recommended by the European Associations for the Study of the Liver (EASL) and Obesity (EASO).19,20

Noninvasive testing methods are often used to identify and diagnose NASH. These methods include the mixed biomarker and patient characteristic Fibrosis-4 (FIB-4) index and NAFLD fibrosis score (NFS), the biomarker based Enhanced Liver Fibrosis (ELF™) score, and imaging tests such as fibroscan. These assessments are described in the Identifying people with NAFLD and Referral and Diagnosis section.

Figure 1.0 Identifying and referring patients with suspected NASH21

Diagnosing NASH using noninvasive methods can present challenges in people with obesity. For example, fibroscan may be less reliable in people with obesity due to technical difficulties caused by increased waist circumference. 21–23 For this reason, liver biopsy may be required to definitively diagnose advanced fibrosis due to NASH in people with obesity.

Referral and management

People with obesity may already be in the care of a healthcare practitioner and as obesity is a major risk factor, these patients should be monitored for NASH.19

People presenting with serum biomarkers suggestive of hepatic inflammation or fibrosis should be referred to a liver specialist, especially if additional risk factors such as T2DM are present.19

In the absence of approved pharmacological treatments, management strategies are closely aligned to those for obesity, namely lifestyle modification. For example, modest reductions in body weight can improve steatosis, with the effect on liver health linked to the percentage of weight lost.24 However, only a minority of people are able to meet this goal unsupervised, and this remains a key challenge in the management of both obesity and NAFLD.25

 

Multidisciplinary management

Given the links between obesity and NASH and the increased presence of comorbidities, people with obesity at risk of NASH may benefit from a multi-disciplinary team (MDT) approach involving primary care, liver specialists, dieticians and other relevant healthcare professionals.

In one study, 64 patients with T2DM whose NAFLD status was unknown were assessed using the NFS.26 Those found to be at risk were referred to a NAFLD MDT clinic for fibroscan assessment. Six patients had a positive fibroscan and underwent liver biopsy. Of these, five were found to have advanced fibrosis, all of whom were obese, with a median BMI of 35.8 kg/m2.26

In this example, an MDT care approach led to new diagnoses of severe asymptomatic NASH. The involvement of dieticians also resulted in weight loss and associated reductions in biomarkers of liver stress, indicating significant improvement of hepatic steatosis.24,26 However, an organised MDT approach is not routine in clinical practice,27 with further studies required to fully assess the potential benefits.

 

Bariatric surgery

Bariatric surgery is an available intervention for morbidly obese people for whom lifestyle intervention has proven ineffective or is not feasible. Aside from the associated weight loss benefits, bariatric surgery has also been proposed as a potential treatment for NAFLD and NASH,19 with some retrospective trials suggesting potential overall benefit.28,29 The lack of randomised clinical trials currently prevents endorsement of bariatric surgery to treat NASH or NAFLD in clinical guidelines.19,30,31

NAFLD and NASH

An overview of the NAFLD and NASH related sections on site.

The Burden of NAFLD and NASH

An overview of NAFLD and NASH in relation to epidemiology, natural history, fibrosis and societal impact.

Identifying people with NAFLD

Tests carried out in primary care on people at risk of NAFLD can help identify people who may need a referral to liver specialists.

Referral and diagnosis

This content focuses on tests in secondary care which can help diagnose advanced fibrosis due to NASH.

Management of NAFLD and NASH

Follow-up for people with NAFLD, lifestyle interventions and surgical interventions for people with NAFLD or NASH.

Diabetes and NASH

Learn more about the identification of NAFLD in people with T2DM, associated comorbidities and specific considerations for management of people with T2DM and NAFLD.

References

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LID/IHQ/18-12//1048d(1) Date of preparation August 2019