Clinical Assessment for High-risk Patients With Non-alcoholic Fatty Liver Disease in Primary Care and Diabetology Practices

Zobair M. Younossi; Kathleen E. Corey; Naim Alkhouri; Mazen Noureddin; Ira Jacobson; Brian Lam; Stephen Clement; Rita Basu; Stuart C. Gordon; Natarajan Ravendhra; Puneet Puri; Mary Rinella; Peter Scudera; Ashwani K. Singal; Linda Henry


Aliment Pharmacol Ther. 2020;52(3):513-526. 

In This Article

Abstract and Introduction


Background: Primary care practitioners (PCPs) and diabetologists are at the frontline of potentially encountering patients with NASH. Identification of those at high risk for adverse outcomes is important.

Aim: To provide practical guidance to providers on how to identify these patients and link them to specialty care.

Methods: US members of the Global Council on NASH evaluated the evidence about NASH and non-invasive tests and developed a simple algorithm to identify high-risk NASH patients for diabetologists and primary care providers. These tools can assist frontline providers in decision-making and referral to gastroenterology/hepatology practices for additional assessments.

Results: The presence of NASH-related advanced fibrosis is an independent predictor of adverse outcomes. These patients with NASH are considered high risk and referral to specialists is warranted. Given that staging of fibrosis requires a liver biopsy, non-invasive tests for fibrosis would be preferred. Consensus recommendation from the group is to risk-stratify patients based on metabolic risk factors using the FIB-4 as the initial non-invasive test due to its simplicity and ease of use. A FIB-4 score ≥1.3 can be used for further assessment and linkage to specialty care where additional technology to assess liver stiffness or serum fibrosis test will be available.

Conclusion: Due to the growing burden of NAFLD and NASH, PCPs and diabetologists are faced with increased patient encounters in their clinical practices necessitating referral decisions. To assist in identifying high-risk NASH patients requiring specialty care, we provide a simple and easy to use algorithm.


From 2015 to 2017, reports from the Center for Disease Control (CDC) indicated that the average life expectancy in the United States (US) has declined mostly due to deaths from drug overdose and suicide.[1,2] Although this mortality rate has now levelled off, chronic diseases remain among the most common causes of death in the US. In this context, obesity (defined as a body mass index [BMI] ≥30 kg/m2 in Western Countries or 27.5 kg/m2 in Eastern Countries) is an important risk for a number of chronic diseases such as cardiovascular diseases, cancers, diabetes (T2DM), and non-alcoholic fatty liver disease (NAFLD).[3–6] The most recent estimates suggest that almost 40% of adults in the US are obese, and obesity is one of the five most common risk factors for global mortality. In fact, the presence of obesity seems to decrease lifespan by 3–8 years, and the addition of diabetes to obesity will reduce lifespan by up to 20 years.[7,8]

In the context of this rising epidemic of obesity, the worldwide prevalence of NAFLD is estimated to be 25%.[9] However, the prevalence can be higher, ranging from 30% up to 90% based on certain risk factors (body composition, presence T2DM, ethnicity, age) and the modality used to establish the diagnosis of NAFLD.[6,10–13] In fact, obesity (regardless of presence of other metabolic factors) is an independent risk factor for NAFLD, and individuals with obesity are at four-folds higher risk of having NAFLD as compared to individuals with normal weight.[14,15] The relationship between increase in weight and risk of NAFLD is dose dependent. In fact, there is a 20% increase risk for NAFLD with for every unit increase in BMI.[16] In addition to obesity, T2DM is another strong risk factor for NAFLD. In a recent meta-analysis, the prevalence of NAFLD among patients with T2DM was found to be 55.5%.[17]

Although, NAFLD is a manifestation of metabolic diseases such as visceral obesity and T2DM, it has been histologically segregated into non-alcoholic fatty liver (isolated hepatic steatosis, NAFL) or non-alcoholic steatohepatitis (NASH) which is defined as steatosis combined with histological features of necroinflammation. Typically, patients with NASH and advanced hepatic fibrosis are those at significant risk for liver-related complications (end-stage liver disease, hepatocellular carcinoma [HCC] and liver transplantation).[18–20] Indeed, numerous studies have shown that the stage of liver fibrosis is the most important determinant of patient outcomes and mortality.[18–21] Considering invasiveness of liver biopsy and the large number of potential patients with NAFLD in the community, liver biopsy is not a practical tool to assess the stage of liver disease in NASH. Over the last several years, established non-invasive tools (NITs) have been used to estimate the stage of liver disease in NASH. These NITs have been found to be helpful to clinicians with the identification of patients at high risk with NASH so that targeted management and long-term monitoring can be accomplished.[22]

On the other hand, it is important to note that the symptomatology of patients with NASH is not always clinically helpful. Although NASH patients can have fatigue, their symptoms are usually nonspecific such that all too often patients are not suspected of having liver disease until they develop advanced stages of cirrhosis. In many instances, patients with NASH, may have had years of minimally elevated alanine aminotransferase (ALT) levels that had been under-appreciated as potentially reflective of a progressive liver disease.43 In other cases, disease progression may have occurred in the absence of any abnormality of aminotransferases. In 2020, despite the high prevalence of NAFLD in the general population, only a very small proportion of patients are identified in the primary care setting in the US.[25]

As a result, these patients are primarily seen in gastroenterology and hepatology practices with advanced disease including cirrhosis and HCC. In this context, NASH has now become the second leading indication for liver transplantation (LT) in the US, while being the most common LT indication among women.[26,27] Furthermore, NASH is recognised not only as the third most common, but also as the most rapidly growing aetiological causes of HCC in the US.[28] Therefore, these data suggest that the hepatic consequences of NASH are already being experienced in clinical practices in the US.

In order to manage this significant public health and clinical challenge, it is becoming increasingly clear that NASH patients who are at highest risk for progressive liver disease must be identified early in their course of disease. In this context, an efficient screening and linkage to the appropriate care strategy to identify these patients from primary care and diabetology practices and link them to 'liver disease' care is important.[25,29,30] This paper provides a summary of a recent meeting by the US members of the Global NASH Council to raise awareness about NAFLD and develop a simple and easy to use algorithm to help with the identification of high-risk patients by primary care providers (PCPs) and non-hepatology specialists.