The growing need for a comprehensive, non-invasive liver health assessment

There exists great need for a non-invasive diagnostic test that can help identify early stage liver disease, both fibrosis and steatosis, in a patient population that is prone to obesity and underlying metabolic disease (type 2 diabetes mellitus, obesity, hypertension, etc.). Recent innovations in rapid, low-cost MR imaging may be that answer.

Liver disease has rapidly emerged as a complex global health challenge, impacting advanced and developing countries alike. Worldwide, nearly one in four people are now known to have abnormal levels of lipid in their liver tissue, a condition known as nonalcoholic fatty liver disease (NAFLD).1 NAFLD is defined as liver fat of greater than 5 percent with no history of excess alcohol consumption and is the precursor of a more advanced form of the disease called non-alcoholic steatohepatitis (NASH), which can lead to liver failure and death. In addition to NAFLD there are many other conditions that can eventually lead to end-stage liver disease such as chronic hepatitis B and C infections, which affect millions of people worldwide.

A recent study reports a five-fold increase in the incidence of NAFLD diagnosis from 1997 to 2014, based on data from the Rochester Epidemiology Project database.2 This explosion in NAFLD and NASH has paralleled the rise in metabolic syndrome worldwide (e.g., type 2 diabetes) and is strongly linked to overnutrition and a sedentary lifestyle.

Part of the challenge is diagnosing NAFLD early, as patients often progress asymptomatically. Researchers are also seeking to better define observed differences in progression rates and directionality of disease advancement. All of this uncertainty makes it difficult to stage NAFLD, stratifying patients based on who might progress from the relatively benign and manageable NAFLD to the more worrisome NASH.

This matters not only in terms of healthier outcomes, but also systemic costs. The transition to NASH hallmarks the point at which modest lifestyle changes are less likely to be effective. There is hope that combination therapies will be able to halt or even reverse NASH progression, but the cost of such strategies is expected to be significant. Moreover, NASH patients remain at heightened risk of cirrhosis, liver decompensation and/or liver cancer — all of which are strongly linked to higher rates of mortality. Because of this, NAFLD and NASH are projected to be the leading cause of end-stage liver disease requiring liver transplantation as early as 2025.3

With the hopes of curtailing this trajectory, the European Union and the US have launched ambitious projects (e.g., LITMUS and NIMBLE) to identify reliable diagnostic approaches for evaluating suspected NAFLD and NASH patients. For decades, liver biopsy has been regarded as the only reliable diagnostic tool, providing a direct histologic assessment of steatosis and fibrosis. However, liver biopsy is invasive, costly and is affected by sampling error and subjectivity in histologic review, making this test a very imperfect gold standard.

Advances in imaging technology have offered alternatives to biopsy in assessing liver fat and fibrosis. Ultrasound-based elastography and attenuation measurements can be used to assess fibrosis and steatosis, respectively, but may be unreliable in NAFLD due to obesity, which is prevalent in over two-thirds of NAFLD patients.4

MR-based solution

MR is stepping up to fill this gap. Two advances in particular have gained consensus in the scientific and clinical community as new gold standards for liver assessment. MR elastography (MRE, MR Touch) for fibrosis staging and proton density fat fraction (PDFF, IDEAL IQ) for steatosis assessment are not only highly accurate, but also perform well in obese patients where ultrasound techniques are often difficult. These MR-based techniques can be combined in a short, efficient exam that has been called a “Hepatogram.”5

Both techniques are individually validated, widely available and recognized in leading gastroenterology and hepatology practice guidelines.6,7 In the past, concerns about cost have hampered the adoption of powerful diagnostics based on MR imaging. But radiology as a medical specialty is embracing the public health challenge of NAFLD and NASH. Thanks to a new CPT code (76391), MRE and PDFF can be done as a rapid, low-cost standalone exam, perhaps marking an exciting trend toward adoption of a pragmatic MR exam that can be used in routine clinical practice for targeted applications.

To assist workflow, researchers have developed a comprehensive analysis tool for MRE and PDFF data that automatically quantifies these critical biomarkers. This tool, which will be made widely available from Resoundant as MREplus+, instantly generates appropriate ROIs and measurements for MRE, PDFF and R2* images based on the optimal data from these acquisitions. The tool outputs these metrics and images in a format that can be used by the interpreting radiologist and provided to the referring physician and patient. The tool provides consistent and repeatable measurements, wellsuited for longitudinal assessments of patients with NAFLD and for clinical trial support.

A new paradigm for MR

While the challenges presented by NAFLD and NASH are enormous, the addition of a rapid, low-cost MR exam is an example of how it is possible to democratize one of medicine’s most powerful technologies — making it more accessible to the millions at risk for these conditions and transforming the way that clinicians and health systems approach the global problem of liver disease.

Disclosure: Dr. Ehman serves as President and CEO of Resoundant, Inc. The Mayo Clinic and Dr. Ehman have intellectual property rights and a financial interest in MRE technology.

References

1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—Meta analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. doi:10.1002/hep.28431.
2. Allen Am, Therneau TM, Larson JJ, Coward A, Somers VK, Kamath PS. Nonalcoholic fatty liver disease incidence and impact on metabolic burden and death: A 20 year-community study. Hepatology. 2018 May;67(5):1726-1736.
3. Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol. 2017 Oct;67(4):862-873.
4. Fazel Y, Koenig AB, Sayiner M, Goodman ZD, Younossi ZM. Epidemiology and natural history of non-alcoholic fatty liver disease. Metabolism. 2016;65:1017–1025.
5. Allen AM, Yin M, Venkatesh SK, et al. SAT-464-Novel multiparametric magnetic resonance elastography (MRE) protocol accurately predicts NAS score for NASH diagnosis. Journal of Hepatology. 2017;66:S659.
6. Lim JK, Flamm SL, Singh S, Falck-Ytter YT. American Gastroenterological Association Institute Guideline on the Role of Elastography in the Evaluation of Liver Fibrosis. Gastroenterology. 2017 May;152(6):1536–1543.
7. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67(1):328-357.