Expert insights from the EASL NAFLD Summit 2019
Dr Javier Ampuero provides his perspective on key sessions from this meeting.
Dr Javier Ampuero (University of Seville, Spain) attended key sessions during the NAFLD Summit, organised by the European Association of the Study of the Liver (EASL), which took place in September 2019 in Seville, Spain. Below he provides his perspective on these sessions and how the learnings may be applied to patient management. Read on to learn more.
Session: The multidisciplinary management of patients with NAFLD – more than one disease?
Nonalcoholic fatty liver disease (NAFLD) is an emerging concern due to its increased prevalence and incidence.1 It is mainly associated with two different conditions: obesity (prevalence of 50%) and diabetes mellitus (prevalence of 25–70%);1–4 however, it can also be associated with other immunological diseases or genetic factors (e.g., PNPLA3 or TM6SF2).1,5,6 Many studies have described the harmful effects of NAFLD, which range from liver damage to increased risk of cardiovascular or kidney disease.7–10 In particular, the risk of advanced fibrosis and hepatocellular carcinoma is two times higher in patients with diabetes mellitus, and it is also increased in people with obesity.8–10 Given the high risk of NAFLD and further complications, national and international guidelines should incorporate its assessment in patients with obesity or diabetes mellitus (e.g., annually performing FIB-4).11–14 Due to the lack of specific therapies for NAFLD, we must implement lifestyle modifications in people with obesity recommending a hypocaloric diet with predominant polyunsaturated over saturated fats and low amount of total fat and can also consider a potentially suitable antidiabetic drug, such as pioglitazone, which has demonstrated a beneficial effect on steatosis, inflammation and fibrosis.15–19
On the other hand, NAFLD is closely related to cardiovascular disease (CVD), ranging from thickening of the intima-media layer of the carotid artery causing arrhythmias. In fact, CVD is the leading cause of mortality in NAFLD patients, particularly in the stages before liver cirrhosis.20,21 Although NAFLD and cardiovascular risk share some epidemiological factors (e.g., obesity, insulin resistance, diabetes mellitus, sedentary lifestyle, arterial hypertension, or dyslipidemia), fatty liver (mainly, NASH) has been independently associated with subclinical and clinical CVD (including fatal and non-fatal events).20,21 Therefore, optimal management of NAFLD would lead to the natural history of both the liver and CVD being modified. National and international guidelines recommend screening for cardiovascular risk factors in NAFLD patients.21,22 The screening of cardiovascular disease in NAFLD is not clearly recommended in these guidelines, although the evaluation of this outcome in high-risk patients (obesity, diabetes, dyslipidemia, and hypertension could be beneficial. Particularly, we should make a rigorous assessment of subclinical CVD in potential candidates for NAFLD-related liver transplantation. One of the most convenient-to-implement tools is the Framingham Risk Score, which allows estimation of the 10-year risk of CVD.23,24 Given the importance of CVD on the prognosis of NAFLD patients, this endpoint should be added and assessed during the development of experimental drugs in clinical trials.
Session: Prevention of NAFLD and public health strategies
The role of primary care physicians is essential to close the disparity between estimated NAFLD prevalence and diagnosis. Usually, the presentation of NAFLD is very heterogeneous, including the incidental finding of steatosis on ultrasound or abnormal liver blood tests.21 Thus, the development of an approach for management of NAFLD patients is crucial to improve the selection of patients with advanced fibrosis and cirrhosis for referral to secondary care, reducing unnecessary referrals, improving the use of healthcare resources and immediate cost savings, and improving patient experiences by avoiding unnecessary clinic appointments and investigations. The referral pathway should be based on the evaluation of liver fibrosis, easily accessible as a first-line test, automatically calculated, inexpensive, and showing a high negative predictive value for advanced fibrosis.
Current guidelines recommend the NAFLD Fibrosis Score (NFS) and FIB-4 index to be used as first-line tools in primary care and non-specialized units to identify patients without advanced fibrosis who do not need further assessment.13,14 By contrast, performance of them to rule in advanced fibrosis is rather inadequate, meaning that further evaluation with another test is required in the event of positive results.13,14 In addition, a significant proportion of patients (around 30%) fall in the intermediate-risk category and cannot be correctly classified.12 This may lead to unnecessary referrals of these patients to liver clinics for further assessment. As such, several studies have tried to combine blood-based testing with imaging biomarkers to improve diagnostic accuracy.24,26,27 Transient elastography, as the most widely available and best evaluated point-of-care technique, is considered the second step in the continuum of care of NAFLD patients.25 It has been proposed that patients at low risk of having advanced fibrosis (<8 kPa) should remain in primary care, while those at high risk of having advanced fibrosis (>8 kPa) should be considered for liver biopsy in secondary care.27
Session: Challenges in the stratification of patients for NAFLD clinical trials
The need for precise stratification in NASH clinical trials lies in the requirement of including patients who will benefit (and not those who will be harmed) and/or in whom the natural history can be improved. To achieve this aim, there are several tools to stratify and predict the risk of NAFLD progression, mainly related to liver damage. Liver biopsy is considered the gold standard to evaluate NAFLD because it is the only tool that can determine steatosis, inflammation, and fibrosis.27 Consequently, it is mandatory to include liver biopsy in clinical trials to date. However, biopsy is being replaced by blood-based non-invasive tests (Hepamet Fibrosis Score, NFS, ELF, FIB-4) and imaging biomarkers (transient and MR elastography) in clinical practice.27 Thus, we will need to move slowly from liver biopsy to non-invasive tests to, consequently, move away from NASH towards liver fibrosis in clinical trials.
Given that liver fibrosis is the essential endpoint and that non-invasive tools have demonstrated the ability to detect fibrosis, and predict NAFLD progression and mortality, they should, at least, complement liver biopsy in clinical trials. However, we should be cautious because the accuracy of non-invasive tests could vary depending on ethnicity, presence of diabetes, or genetics.
On the other hand, to identify the most effective therapeutic intervention in patients with NAFLD and associated metabolic comorbidities is challenging. Current clinical management simply addresses individual components of the underlying complex metabolic disorder.13,14 Moreover, treatment decisions are non-personalised and frequently do not consider the status of dysmetabolic comorbidities. New strategies need to be adopted to integrate the spectra of comorbidities usually present in NAFLD patients to be able to develop personalised multicomponent therapeutic approaches. This would allow targeting of different elements that increase the chances of achieving NASH resolution and/or reversion of severe histological outcomes and reduce not only liver-related but also metabolic syndrome-associated morbidity and mortality.
Dr Ampuero was sponsored by Gilead to attend these sessions and prepare this piece; Gilead has reviewed this material to ensure accuracy but the views are Dr Ampuero’s own. Opinions expressed in this article represent those of Dr Ampuero.
- Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64(1):73–84.
- Targher G, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007;30:1212–1218.
- Williamson RM, et al. Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: The Edinburgh type 2 diabetes study. Diabetes Care 2011;34:1139–1144.
- Dai W, et al. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Medicine 2017;96:e8179.
- Mann J and Anstee Q. NAFLD: PNPLA3 and obesity: a synergistic relationship in NAFLD. Nat Rev Gastroenterol Hepatol 2017;14:506–507.
- Goffredo M, et al. Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study. Hepatology 2016;63:117–125.
- 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.
- Sweet PH, et al. Nonalcoholic Fatty Liver Disease. Prim Care Clin Off Pract 2017;44:599–607.
- Hui J, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 2003;38:420–427.
- Adams LA, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113–121.
- McPherson S, et al. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic liver disease. Gut 2010;59:1265–1269.
- Shah A, et al. Use of the FIB4 index for non-invasive evaluation of fibrosis in nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009;7:1104–1112.
- EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64(6):1388–1402.
- Non-alcoholic fatty liver disease (NAFLD). Available at: https://cks.nice.org.uk/non-alcoholic-fatty-liver-disease-nafld#!scenario. (last accessed October 2019).
- Petersen KF, et al. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005;54:603–608.
- Promrat K, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010;51:121–129.
- Kantartzis K, et al. High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease. Gut 2009;58:1281–1288.
- Sanyal AJ, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675–1685.
- Boettcher E, et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2012;35:66–75.
- Oni ET, et al. A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care? Atherosclerosis 2013;230:258–267.
- Wong CR, Lim JK. The Association Between Nonalcoholic Fatty Liver Disease and Cardiovascular Disease Outcomes. Clin Liver Dis (Hoboken) 2018;12(2):39–44.
- Abeles RD, et al. Derivation and validation of a cardiovascular risk score for prediction of major acute cardiovascular events in non-alcoholic fatty liver disease; the importance of an elevated mean platelet volume. Aliment Pharmacol Ther 2019;49(8):1077–1085.
- Treeprasertsuk S, et al. The Framingham risk score and heart disease in nonalcoholic fatty liver disease. Liver Int 2012;32(6):945–950.
- Petta S, et al. The combination of liver stiffness measurement and NAFLD fibrosis score improves the noninvasive diagnostic accuracy for severe liver fibrosis in patients with nonalcoholic fatty liver disease. Liver Int 2015;35(5):1566–1573.
- Afdhal N. Fibroscan (Transient Elastography) for the measurement of liver fibrosis. Gastroenterol Hepatol 2012;8:605–607.
- Petta S et al. Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver fibrosis in patients with NAFLD. Aliment Pharmacol Ther 2017;46(6):617–627.
- Castera L, et al. Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 2019;156(5):1264–81.e4.
LID/IHQ/19-09//1072a • Date of Preparation: October 2019