Early detection, monitoring, and noninvasive diagnostic testing are essential to controlling this epidemic

By Amreen Dinani, MD

Nonalcoholic fatty liver disease (NAFLD), an umbrella term for a range of liver conditions that occurs as a result of fat in the liver, affects approximately 25% of the worldwide population and 100 million individuals in the United States.1Its more serious form, nonalcoholic steatohepatitis (NASH), affects 6% of the global population2 and is expected to increase by 63% by 2030.3

NAFLD can cause inflammation of the liver, liver tissue damage, and liver scarring (fibrosis), which in turn can lead to cirrhosis and liver cancer (hepatocellular carcinoma). This burgeoning disease is on track to become the leading cause of liver transplantation in the United States. 

NAFLD is often asymptomatic in its earliest stages. When patients feel well, it can be challenging for physicians and caregivers to convince them they may have a potentially dangerous and progressive condition. 4

Clinical laboratories have been one of the frontline partners in identifying common liver diseases, such as chronic hepatitis C, and they well positioned to play a key role in disease identification, risk stratification, and long-term follow-up of NAFLD.

An example of this is the adoption of viral load and genotype testing to inform treatment decisions with direct-acting antiviral agents. Clinical labs are consistently among the first to recognize new challenges, adopt the latest technologies, and promote innovative solutions. Recent advances in diagnosis and treatment are making it possible for both primary care and specialists to play an active role in managing patients with NASH.

Growing Need for Early Detection 

The rise in NAFLD closely mirrors the obesity and type 2 diabetes epidemic. Obesity and type 2 diabetes are the leading risk factors for NAFLD. The Hispanic population has been identified as a high risk population for NAFLD and NASH, related to high metabolic disease burden and genetic predisposition. The leading causes of mortality in non-cirrhotic NAFLD is cardiovascular disease and non-liver related cancers5 and liver-related complications in those with cirrhosis. 

Primary care physicians can play a central role in identifying patients atrisk for NAFLD. Furthermore, they can assist in managing metabolic comorbididites such as obesity and type 2 diabetes. Other subspecialties that encounter these patients at risk for NAFLD are endocrinology, cardiology, and bariatric medicine. 

Noninvasive methods to detect NAFLD and liver fibrosis are being adopted more commonly to screen and detect NAFLD.This painless approach to screening can be performed in the doctor’s office as part of an annual exam. It can also be used to motivate and guide individuals to achieve weight loss, lifestyle goals and manage medical comorbidities.7

Diagnosing NAFLD/NASH

NAFLD is a complex disease with a varied presentation, ranging from simple steatosis to steatohepatitis, the latter typically associated with fibrosis and cirrhosis. There are no specific clinical symptoms or laboratory tests to make the diagnosis. 

Liver biopsy is the standard to make the diagnosis of NAFLD, NASH (steatosis, inflammation, and liver cell injury), and liver fibrosis. Biopsy also remains the cornerstone criterion for including patients with NAFLD in clinical trials and determining efficacy of therapeutic targets in drug development. 

The broad applicability of liver biopsies is however limited because 1) the burden of NAFLD in the general population is overwhelming; 2) the procedure is invasive and associated with patient discomfort, such as pain, potential bleeding, and other complications; 3) only a portion of the liver is sampled, which can be ineffective because the disease is heterogonous; and 4) biopsies are not ideal to monitor disease and effectiveness of therapies.  

Innovative methods are needed to diagnose, guide management, and follow up with these patients. In fact, there is a need to develop noninvasive tests (NITs) to diagnose the disease in a way that is simple, inexpensive, easy to interpret, able to be monitored long-term, and widely applicable to a general population. 

Noninvasive Tests

NITs are reproducible, widely available, and relatively low-cost.

• Fibrosis 4 Index (FIB4) is a blood-based NIT that can be used for screening to rule out advanced fibrosis. It is comprised of a basic patient information, such as age, routinely obtained blood tests ( liver enzymes [aspartate aminotransferase (AST) and alanine transaminase (ALT)], and platelet counts). Other serum-based NITs include NALFD Fibrosis Score (NFS), BARD, and AST/ALT ratio.8

• Vibration controlled transient elastography (VCTE) is an imaging-based technology that has emerged to measure liver stiffness and fat measurements by propagation of a vibration wave through the liver. The amount of liver fat can be quantified with controlled attenuated parameter (CAP), an added feature of VCTE. The challenge is that this approach requires an additional diagnostic procedure to determine if the patient has NAFLD. This model also relies on ultrasound to detect fat, which adds cost and complexity to the diagnostic pathway. 

• The FibroScan-AST (FAST) score is an added feature to VCTE that incorporates AST, VCTE, and CAP to determine probability of active fibrotic-NASH. This score combines circulating biomarkers, such as AST with VCTE and CAP, to determine probability of active fibrotic-NASH in patients suspected of having NAFLD. Scores such as FAST can streamline the diagnostic pathway, reducing patient burden and wasteful diagnostic procedures. 

Treatment Options for NAFLD

NAFLD is reversible if identified early and accompanied by lifestyle change. Screening and early detection can help to prevent more serious conditions, such as end-stage liver disease and liver cancer.Weight loss is the best treatment option for NAFLD and prevention of fibrosis, although it can be difficult to maintain. Several studies, followed by comprehensive meta-analysis, eloquently illustrate the beneficial effecst of weight loss on liver fat, inflammation, and NASH.9

There are innumerable pharmacological therapies being studied to treat NAFLD. While none have been approved, there are several molecules with much promise. In the meantime, creative ways need to be implemented to help patients achieve weight loss and manage their medical metabolic comorbidities. 

Labs as Diagnostic Partners

Clinical labs are partnering with physicians and specialists to take on a role in the fight to manage this growing disease.

Commercial organizations are facilitating connections among clinical labs, scientists, and product developers; aiding in the transfer of human biospecimens from clinical labs to research labs; helping researchers define criteria for clinical trials based on deidentified data gathered from global sources; and serving as interpreters of data to facilitate a better understanding of clinical pathways and treatments.10 

Amreen Dinani, MD, Icahn School of Medicine at Mount Sinai.

Amreen Dinani, MD, is an assistant professor in the Department of Medicine, Division of Liver Diseases at Icahn School of Medicine at Mount Sinai. Her clinical and research interests are in nonalcoholic fatty liver disease (NAFLD), and she is an investigator for many ongoing clinical trials in NALFD. Previously, at Dartmouth Hitchcock Medical Center, Dinani introduced noninvasive markers of liver fibrosis and vibration controlled transient elastography, and she was instrumental in developing a Fibrosis-4 calculator into the organization’s electronic medical records system to streamline NAFLD patient identification.


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2. NASH Education Program. How Prevalent Is NASH? Available at: https://www.the-nash-education-program.com/what-is-nash/how-prevalent-is-nash/. Accessed March 10, 2021. 

3. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123-133. doi: 10.1002/hep.29466

4. Houghton-Rahrig L, Schutte D, von Eye A, et al. Exploration of a symptoms experience in people with obesity-related NAFLD. Nurs Outlook.2013;(61)4;242-251. doi: 10.1016/j.outlook.2013.05.003

5. Pan JJ, Fallon MB. Gender and racial differences in nonalcoholic fatty liver disease. World J. Hepatol. 2014; 6(5):274–283. doi: 10.4254/wjh.v6.i5.274.

6. Seeff LB, Everson GT, Morgan TR, et al. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol. (2010);8(10):877-883. doi: 10.1016/j.cgh.2010.03.025.

7. De Franchis R. Non-invasive (and minimally invasive) diagnosis of oesophageal varices. J Hepatol. 2008;49(4):520-527. doi: 10.1016/j.jhep.2008.07.009.

8. Yoon KC, Kwon HD, Jo HS, et al. Explorative study of serum biomarkers of liver failure after liver resection. Sci Rep. 2020;10(1):9960. doi: 10.1038/s41598-020-66947-1.

9. Promrat K, Kleiner DE, Niemeier H, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51(1):121-129. doi: 10.1002/hep.23276.

10. Torchilin K. Clinical labs and the rise of precision medicine. Clinical Lab Products. July 10, 2017. Available at: https://clpmag.com/diagnostic-technologies/molecular-diagnostics/clinical-labs-rise-precision-medicine/. Accessed March 9, 2021.