Obesity and NASH
Liver health can sometimes be overlooked in people with obesity, where cardiovascular and endocrinological complications take priority. However, the prevalence of nonalcoholic fatty liver disease (NAFLD) is higher in people with obesity compared with the general population, and up to one quarter of obese people with NAFLD go on to develop nonalcoholic steatohepatitis (NASH).
Obesity can also exacerbate genetic predisposition to fatty liver and fibrosis, increasing the risk of developing cirrhosis. It is therefore important to consider hepatic outcomes in people with obesity and develop management strategies to avoid potentially serious implications of concomitant obesity and NAFLD.
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
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
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
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
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
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 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.
- Younossi Z, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.
- Vernon G, et al. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011;34:274–85.
- Cortez-Pinto H, et al. Non-alcoholic fatty liver: another feature of the metabolic syndrome? Clin Nutr 1999;18:353–8.
- Ong J, et al. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg 2005;15:310–5.
- Lazo M and Clark J. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 2008;28:339–50.
- Wanless I and Lentz J. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990;12:1106–10.
- Mann J and Anstee Q. NAFLD: PNPLA3 and obesity: a synergistic relationship in NAFLD. Nat Rev Gastroenterol Hepatol 2017;14:506–507.
- Yki-Järvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol 2014;2:901–10.
- Goffredo M, et al. Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study. Hepatology 2016;63:117–25.
- Elliott S, et al. Fructose, weight gain, and the insulin resistance syndrome. Am J Clin Nutr 2002;76:911–22.
- Ouyang X, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol 2008;48:993–9.
- Abdelmalek MF and the Nonalcoholic Steatohepatitis Clinical Research Network. Increased fructose consumption is associated with ﬁbrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 2010;51:1961–71.
- Hashimoto E, et al. Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. J Gastroenterol 2009;44:89–95.
- Musso G, et al. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med 2014;11:e1001680.
- Reitman M, et al. Leptin in the liver: a toxic or beneficial mix? Cell Metab 2012;16:1–2.
- Medici V, et al. Increased soluble leptin receptor levels in morbidly obese patients with insulin resistance and nonalcoholic fatty liver disease. Obesity 2010;18:2268–73.
- Ascha M, et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51:1972–8.
- Noureddin M and Rinella M. Nonalcoholic Fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clin Liver Dis 2015;19:361–79.
- European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388–402.
- Yumuk V, et al. European Guidelines for Obesity Management in Adults. Obes Facts 2015;8:402–24.
- Castéra L, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010;51:828–35.
- Cassinotto C, et al. Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, Fibroscan, and ARFI with liver biopsy. Hepatology 2016;63:1817–27.
- Wong G, et al. Factors associated with unreliable liver stiffness measurement and its failure with transient elastography in the Chinese population. J Gastroenterol Hepatol 2011;26:300–5.
- Harrison S, et al. Orlistat for Overweight Subjects with Nonalcoholic Steatohepatitis: A Randomized, Prospective Trial. Hepatology 2009;49:80–6.
- Vilar-Gomez E, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterol 2015;149:367–78.
- Armstrong M, et al. Severe asymptomatic non-alcoholic fatty liver disease in routine diabetes care; a multi-disciplinary team approach to diagnosis and management. Quart J Med 2014;107:33–41.
- Marchesini G, et al. Review article: the treatment of fatty liver disease associated with the metabolic syndrome. Aliment Pharmacol Ther 2005;22:37–9.
- Mathurin P, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterol 2009;137:532–40.
- Mummadi R, et al. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and metaanalysis. Clinical Gastro and Hepatol 2008;6:1396–402.
- Chalasani N, et al. The Diagnosis and Management of Non-Alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Gastroenterol 2012;142:1592–609.
- Chavez-Tapia N, et al. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database of Systematic Reviews 2010;CD007340.
LID/IHQ/18-12//1048d(1) Date of preparation August 2019