Nonalcoholic steatohepatitis medical patient journey from the perspective of hepatologists, gastroenterologists and patients: a cross-sectional survey

Nonalcoholic steatohepatitis (NASH) is the inflammatory form of nonalcoholic fatty liver disease (NAFLD). Both NAFLD and NASH are characterized by identification of > 5% hepatic steatosis in the absence of excessive alcohol consumption and other etiologies [1]. NASH is characterized by steatosis accompanied by hepatocyte inflammation and injury (ballooning) [1], which can perpetuate the development of fibrosis. The extent of liver fibrosis is the greatest predictor of hepatic morbidity and mortality [2‐6]. Both NAFLD and NASH can develop progressive hepatic fibrosis, though this is more likely in the context of NASH [7‐9].

Globally, 25% of people are estimated to have NAFLD and 2–6% are estimated to have NASH [10]. In the US, NAFLD prevalence is estimated at 37%; among patients with NAFLD, approximately 8% have advanced liver fibrosis [11]. The prevalence of NASH is increasing, but more concerning is the disproportionate increase in those with advanced fibrosis, hepatocellular carcinoma, and hepatic decompensation predicted by modeling studies [12]. In the United States, NASH is currently the leading indication for liver transplant in women and those > 65 years of age and is predicted to become the overall leading indication for liver transplant [13]. While there are currently no FDA approved pharmacologic treatments for NASH [14], management focused on optimal control of comorbidities, using available therapies that may have additive benefit in NASH, as well as implementation and sustained support for lifestyle change can improve liver health and overall health in patients with NASH [14].

NASH is underdiagnosed as patients are often asymptomatic or present with non-specific symptoms [15]. According to 2018 American Association for the Study of Liver Diseases (AASLD) guidance, NAFLD can be diagnosed by imaging or liver biopsy while NASH requires a liver biopsy [1]. Many patients and healthcare professionals (HCPs) are hesitant to use liver biopsies due to costs and associated risks [16]. The requirement for liver biopsy to confirm diagnosis could be contributing to the under-diagnosis of NASH; liver biopsies are potentially dangerous, resource-intensive, and have limited scalability [17]. The field is looking to non-invasive tests (NITs) to identify those at most risk, who can then be targeted for therapy or more confidently exclude those who do not need specialty care [18]. Noninvasive risk stratification algorithms using calculations (e.g., Fibrosis-4 Index [FIB4]) followed by liver stiffness measurements in those with type 2 diabetes mellitus or high risk, are being proposed and refined to aid HCPs in their management [18, 19].

This study seeks to understand the medical journeys of patients with NASH, the role of hepatologists and gastroenterologists in diagnosing and treating patients with NASH, and to identify areas for improvement in the diagnosis and treatment of NASH in the United States (US).

NASH is a growing problem and will likely be the primary cause of liver transplant in the near future [13]. To meet the needs of this growing patient population and curb the increase, awareness must be raised, diagnosis rates increased, and treatments improved. Across the different groups of HCPs we queried, the majority within each group view themselves as the coordinator of care for patients with NASH suggesting that the clinical roles and responsibilities are unclear, but the majority are willing to take on the challenge of managing NASH. Hepatologists and gastroenterologists can take leadership in defining care pathways.

Most patients reported that hepatologists and gastroenterologists conducted the tests that led to diagnosis and officially diagnosed them with NASH. Patients and other HCPs want a physician specializing in NASH to support treatment. Patients with more severe fibrosis have an increased risk of morbidity and mortality [2, 3]. Quantification of hepatic fibrosis provides an indication of current risk level and can inform the treatment plan of patients with NASH [18, 19]. The extent of fibrosis is an important metric of NASH improvement or worsening. Hepatologists and gastroenterologists were more likely than other HCPs to distinguish between NASH with and without fibrosis. This may reflect a better understanding of the disease or greater access to tools for the evaluation of fibrosis.

Hepatologists and gastroenterologists should work to improve communication of test results to patients. In our study many patients with NASH (44%) reported that they received diagnoses of NASH without qualifiers (e.g., a diagnosis of NASH rather than NASH with moderate/severe fibrosis). This suggests that a key role for hepatologists and gastroenterologists is to define disease progression and prognosis more specifically and that the stage of a patient’s liver disease may inform their treatment strategy.

Hepatologists and gastroenterologists can use their expertise in clinical practice guidance and knowledge of the importance of fibrosis evaluation to lead/guide care for patients with NASH. Hepatologists and gastroenterologists are leading efforts to modify existing guidance and develop new guidance for primary care to support initial diagnosis and referrals to specialists. New AASLD and AGA guidance emphasizes the importance of algorithmic diagnostic pathways that emphasize NITs and reserve liver biopsies for high-risk patients where NITs have proved inconclusive [18, 19]. There is room to use NITs such as FIB-4 derived from routine clinical variables (e.g. age, blood tests etc.) to assist in the identification of fibrotic NASH [15]. Transient elastography is a relatively inexpensive NIT and our study shows that it is already highly used by hepatologists and gastroenterologists [21].

Hepatologists and gastroenterologists face a number of challenges in diagnosing and treating NASH. NASH is underdiagnosed [22]; the current requirement for liver biopsy to diagnose NASH may be a barrier to more frequent NASH diagnosis [17]. Although a liver biopsy is the reference standard for the diagnosis of NASH [1], many of the patients in our study (47%) said they did not receive a biopsy to establish their NASH diagnosis. Determining when and where the risk associated with a biopsy is deemed appropriate is largely a judgment call, though several algorithms have been proposed [18, 23]. Work remains to be done to educate all HCPs on the appropriate method of risk stratification in the context of NAFLD.

NASH is a chronic condition that requires regular monitoring and management [24]. Frequent follow-ups and a multi-pronged approach are important for managing these diseases [25]. In this study, hepatologists and gastroenterologists had the lowest frequency of follow-up appointments suggesting more frequent touchpoints with patients might require a different care management paradigm. A longitudinal study of Japanese patients with NAFLD found that use of insulin and decrease in hemoglobin A1C levels were significantly associated with reductions in liver fibrosis [26]. Similarly, weight loss achieved with anti-obesity medications [27], lifestyle changes [28], or bariatric surgery [29] can have a positive impact on NASH. Inexperience with anti-obesity medications may be preventing hepatologists and gastroenterologists from utilizing all available resources to treat NASH [27]. Experts believe that a multidisciplinary approach involving dietitians, behavioral therapists, and physical activity supervisors is important to successful NAFLD/NASH management [30]. The aim is to improve the effectiveness of lifestyle change by improving the counselling and advice patients receive, providing actionable diet and weight loss strategies, and supporting patients as they attempt to make lifestyle changes.

Survey research provides a unique perspective on how patients and HCPs interact with the healthcare system but comes with limitations. Self-reported experiences may reflect inaccurate or incomplete recollection on the part of survey participants [31]. The groups of HCPs and patients with NASH we surveyed are unpaired: the HCPs were not matched with patients they were treating. In some instances, HCPs and patients appear to disagree about the frequency with which certain events occur (e.g., tests conducted to diagnose NASH). Sometimes these differences may reflect differences in perception between HCPs and patients. Other times, these differences may reflect real differences in the HCP and patient populations sampled. The patients and physicians who responded to this survey may differ in important ways from those who did not respond to this survey; this could limit the generalizability of these findings to the wider population of patients with NASH and physicians treating NASH in the US.

Hepatologists and gastroenterologists have unique clinical roles, which have not been explored in this study. This study involved a total of 75 respondents for these specialties that included 64 gastroenterologists and 11 hepatologists. Hepatologists and gastroenterologists were grouped to provide meaningful numbers for evaluation. However, grouping gastroenterologists and hepatologists together limits our ability to provide insights for each specialty and may be hiding important differences between the two types of specialists and how they manage patients with NASH.

Hepatologists and gastroenterologists can leverage their roles as coordinators of care for patients with NASH to encourage better practices for diagnosis and treatment. The diagnostic process is highly variable; many different diagnostic tests are used to confirm NASH diagnosis. There is room for improvement and standardization in NASH diagnosis. Utilization of NITs and risk stratification algorithms may lead to diagnosis of more patients with NASH and at earlier stages of disease and new guidance from professional medical societies represents a step in the right direction by advocating increased use of NITs. Hepatologists and gastroenterologists can advocate greater use of medications for diabetes, obesity, and other comorbidities where appropriate to tackle the growing problem of NASH. Hepatologists and gastroenterologists should embrace a multidisciplinary approach to NASH treatment and national guidance should be updated to clearly define roles and responsibilities of various clinicians [18, 32].