Abstract and Introduction
There is ongoing recognition of the burden of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), with fibrosis being the most important histological feature that is associated with progression to cirrhosis and the occurrence of major adverse liver outcomes. Liver biopsy is the gold standard applied to detect NASH and determine the stage of fibrosis, but its use is limited. There is a need for non-invasive testing (NIT) techniques to identify patients considered at-risk NASH (NASH with NAFLD activity score > 4 and ≥ F2 fibrosis). For NAFLD-associated fibrosis, several wet (serological) and dry (imaging) NITs are available and demonstrate a high negative predictive value (NPV) for excluding those with advanced hepatic fibrosis. However, identifying at-risk NASH is more challenging; there is little guidance on how to use available NITs for these purposes, and these NITs are not specifically designed to identify at-risk NASH patients. This review discusses the need for NITs in NAFLD and NASH and provides data to support the use of NITs, focusing on newer methods to non-invasively identify at-risk NASH patients. This review concludes with an algorithm that serves as an example of how NITs can be integrated into care pathways of patients with suspected NAFLD and potential NASH. This algorithm can be used for staging, risk stratification and the effective transition of patients who may benefit from specialty care.
Non-alcoholic fatty liver disease (NAFLD) is defined as the presence of steatosis in ≥5% of hepatocytes, without significant alcohol consumption or other known causes of steatosis. NAFLD is subdivided into two primary subtypes, the fairly benign non-alcoholic fatty liver (NAFL) and the more severe, progressive form termed non-alcoholic steatohepatitis (NASH), defined histologically by steatosis in ≥5% of hepatocytes, lobular inflammation and liver cell injury (hepatocyte 'ballooning'), with or without fibrosis. Until recently, there was a lack of large prospective studies to establish the prevalence of NAFLD and NASH. A recent study used magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) to screen for NAFLD and the gold standard reference biopsy to screen for NASH. The cohort included 664 asymptomatic, middle-aged adults (mean age: 56 ± 6.4 years, 50% male, mean body mass index [BMI]: 30.48 ± 5.46 kg/m2, 52% obese). Investigators determined that the overall prevalence of NAFLD was 38% and that of NASH by biopsy was 14%. These estimates are higher than those previously reported; in 2016, the global prevalence rates of NAFLD and NASH were estimated at 25% and 1.5–6.45% respectively. A more recent meta-analysis suggests that the global prevalence of NAFLD is approximately 30%. The growing prevalence of NAFLD and NASH may partly be owing to the increasing prevalence of associated comorbidities. Metabolic comorbidities associated with NAFLD and NASH include obesity, type-2 diabetes mellitus (T2DM), dyslipidaemia, hypertension and metabolic syndrome (MetS).[3,5] The prevalence of NAFLD in patients with T2DM or MetS is estimated at over 50%, but when confirmed using biopsy, it has been found to be over 90% in these populations.
There are significant knowledge gaps regarding the diagnosis, natural history and treatment of NAFLD, but it is known that NAFLD is considered 'dichotomous'. NAFL poses lower risk to the patient, from a liver-related perspective, while NASH may lead to progressive hepatic fibrosis, liver cirrhosis, liver failure and hepatocellular carcinoma (HCC).[1,8,9] An analysis of Medicare claims between 1999 and 2012 found that NAFLD was the most common cause of chronic liver disease (CLD) in all ethnic groups combined (52%). The most important histological feature of NAFLD associated with long-term mortality is fibrosis, and NAFLD has been found to be one of the most common causes of cirrhosis leading to liver transplants, second only to alcohol-associated liver disease. Another study found that the number of new waitlisted liver transplant registrants with NAFLD increased by 170% from 2004 to 2013. NASH has become the most common cause of cirrhosis in adults, the second leading cause for waitlisting and liver transplants in all patients and the first leading cause for waitlisting and liver transplants among Asian, Hispanic and non-Hispanic white females.
Identifying the presence of significant fibrosis (≥F2 fibrosis, NAFLD activity score [NAS] > 4) as a result of NASH in high-risk patients is of utmost importance, given its prognostic value and correlation with progression to cirrhosis and major adverse liver outcomes (MALOs). Liver biopsy is the gold standard applied to detect fibrosis, but its use is limited. Several non-invasive tests (NITs) are available for this purpose, which include 'wet' (i.e., NITs that use serum biomarkers to identify fibrosis) and 'dry' (i.e., NITs that use imaging to identify fibrosis). These NITS demonstrate high accuracy when used in combination, but staging and risk stratification of NASH are more challenging; there is no guidance on how to use available NITs for these purposes. This review discusses the need for NITs in NAFLD and NASH and provides data to support the use of NITs, focusing on newer methods of non-invasively identifying at-risk NASH patients (≥F2 fibrosis, NAS ≥4). This review concludes with an algorithm that serves as an example of how NITs can be integrated into care pathways of patients with NAFLD for better staging and risk stratification, as well as inform the referral decision for further evaluation.
Liver International. 2023;43(5):964-974. © 2023 Blackwell Publishing