An alarming trend is emerging around the world: approximately two billion adults are obese or overweight and over 400 million have diabetes, with associated liver disease accounting for approximately two million deaths per year worldwide. Both obesity and diabetes are risk factors for two asymptomatic liver diseases: non-alcoholic fatty liver disease (NAFLD) and its more severe form, non-alcoholic steatohepatitis (NASH). It is estimated that 85 million Americans have NAFLD and about 16 million have NASH with some level of fibrosis. Due to this high prevalence rate, NASH has become one of the most common etiologies for liver cancer and a leading indication for a liver transplant.
NAFLD and NASH are conditions in which fat builds up in the liver. NASH is a progressive and burgeoning liver disease that can lead to increased liver-related mortality and morbidity. Data suggest that when a patient progresses to fibrotic NASH, their eight-year mortality rate increases to 35% or a seven-fold increase over NAFLD alone. Moreover, people with Type 2 diabetes have a 7-8 fold risk of advancing from NAFLD to fibrotic NASH.
These numbers are a call to arms for clinical laboratories, which have served as frontline partners in the battle against other common liver diseases such as Hepatitis C (HCV). For instance, laboratories played a critical role in supporting and promoting 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.
Innovative Technology Advances Diagnosis and Monitoring
Fortunately, NAFLD can be reversible if caught in the early stages. Innovative, non-invasive examination technology, such as the FibroScan and FAST Score, make it possible to quickly assess and monitor liver health: FibroScan is a rapid, point-of-care liver examination and FAST Score is a FibroScan-based probability score to help identify patients with active fibrotic-NASH.
FibroScan provides a quantitative assessment of liver fat and stiffness that helps to identify patients who are likely to benefit from pharmacologic therapy. The FibroScan examination can be performed in virtually any point-of-care setting, streamlining the time to diagnose and reducing the costs associated with liver biopsy or other expensive testing.
NAFLD/NASH in the Lab
NAFLD is a complex disease process that can also be observed in non-obese individuals and in patients without clinical manifestations of the metabolic syndrome. What’s more, NAFLD carries both metabolic and liver-specific complications that make the approach to care unique among medical conditions.
When it comes to diagnosis and the selection of a therapeutic regimen, the complexity of NAFLD and NASH results in a number of uncertainties. Unlike the diagnosis of Hepatitis C, where refractory testing of antibody-positive blood samples can be followed immediately by a determination of viral load and genotype, the diagnosis of NAFLD and NASH is more complicated and non-invasive testing may require a combination of direct and indirect biomarkers. With the high rates of suspected disease, having cost-effective and simple to interpret tools available to HCPs is critical.
Recent advances in diagnosis and treatment, however, are making it possible for both primary care physicians and medical specialists, such as endocrinologists and cardiologists, to play a more active role in managing patients with Type 2 diabetes and NASH.
Clinical laboratories also have an important role to play in this process. If a patient’s blood test reveals a diagnosis of diabetes, for instance, laboratorians are well-positioned to advise the primary care physician that the patient should also be screened for liver disease. Sharing their expertise and knowledge about liver disease assessment is a way that labs can differentiate themselves as essential partners in the management of this chronic disease.
Labs are also well positioned to share with healthcare personnel and colleagues the latest and most effective testing technologies available, such as FibroScan and FAST.
Closer Look at FibroScan
As an alternative to liver biopsy and other tests, more than 3,000 peer-reviewed research publications position FibroScan as the most widely studied tool for liver assessment in point of care. Clinicians and researchers are exploring the use of FibroScan to examine and identify patients with NASH who are at risk of progression to cirrhosis, improve the detection of fibrosis among NAFLD patients, and determine how the use of the technology in physicians’ offices and other point-of-care settings can improve the cost-effectiveness of the procedure.
An interim look at an ongoing study of 10,000 patients with no history of liver disease was conducted in community-based endoscopy centers by the Florida Research Institute. Based on a FibroScan assessment alone, only 43% of the patients evaluated had what were considered normal livers, while the remainder had some form of liver abnormality ranging from elevated liver fat to liver fibrosis. This analysis of the first 367 patients suggests a significant rate of undiagnosed NAFLD in the population studied.
FAST Score Enhances Role of FibroScan
Because of the complexity of diagnosis, active fibrotic NASH, coupled with the difficulties that clinical trial professionals face in identifying the most at-risk patients, demands greater innovation. Recent evidence shows that one tool, the FAST Score could not be more timely. Featured in The Lancet Gastroenterology & Hepatology, “FibroScan-AST (FAST) Score For The Non-Invasive Identification Of Patients With Non-Alcoholic Steatohepatitis With Significant Activity And Fibrosis: A Prospective Derivation And Global Validation Study” reviews a prospective study including 1,400 patients undergoing a liver biopsy.
This publication demonstrates the power of combing direct and circulating biomarkers to enhance the diagnostic capabilities of healthcare providers to efficiently identify patients with a high probability of active fibrotic NASH and better target more expensive or more invasive diagnostic procedures – saving time and resources for clinicians by eliminating patients who don’t need additional assessment.
The FAST Score can be repeated periodically and the examination with FibroScan is covered by most insurance every six months, so patients with indeterminate results can be routinely monitored. The FAST Score is not intended to replace clinical judgment, but rather is designed to provide additional insights by uniquely combining three components:
- Two physical biomarkers: liver stiffness by VCTE™ and controlled attenuation parameter (CAP)™, estimating fibrosis and steatosis from an examination with FibroScan
- AST (aspartate aminotransferase), a readily available blood marker of inflammation
The FAST score provides healthcare providers with an efficient and cost-effective tool to help non-invasively identify at-risk patients with progressive NASH – those individuals that merit consideration for further treatment or monitoring for those at risk of progressive liver disease.
Drug Development
The FAST Score comes at a time when efficient identification of active fibrotic NASH poses a challenge for drug companies, many of which are now developing drugs targeting this disease.
As many as 50% of the patients sent to biopsy were not appropriate candidates for clinical trials. Historically, there had been a high screen failure rate at liver biopsy because of the absence of such tools as the FAST Score.
The FAST score can not only reduce unnecessary specialist referrals and invasive tests, such as liver biopsies in patients unlikely to have significant diseases, but it will also help to more efficiently identify the patients suitable for clinical trials and emerging therapies.
This tool will also impact the development and introduction of several compounds to treat NALFD and the liver complications of NASH. The first drugs will be expensive and may be able to reverse fibrosis in less than half of the patients treated. The FAST score is the first of several scores that will combine FibroScan with blood biomarkers that answer different questions along the treatment journey. For monitoring, it is likely that we will see VCTE and CAP quantitative assessments combined with more complex blood biomarkers to create Non-Invasive Tests (NITs) to enhance the assessment of liver health. These NITs may more rapidly and accurately differentiate those patients benefiting from treatment from those who are not.
Experts anticipate that over the next few years, the pharmaceutical treatment market for NAFLD could potentially reach $35 billion. Accurate, ongoing assessment of liver fat and stiffness will become even more critical in the anticipated prescribing of drugs.
Labs as Diagnostic Partners
In the fight against liver disease, clinical labs are partnering with primary care physicians and specialists to take on an expanded role. In this arena, labs have found additional opportunities to contribute to research by working with commercial organizations. They 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 de-identified data gathered from global sources; serving as interpreters of data to facilitate a better understanding of clinical pathways and treatments.
Although most patients are asymptomatic, NASH is sometimes associated with abdominal pain, fatigue, and other rare symptoms. Elevated liver enzymes in the blood may be associated with the disease but are not always a sign of liver disease or an indication of its severity.
Physicians often rely on elevations in alanine transaminase (ALT) levels. Unfortunately, elevated ALT levels alone are not sufficient for identifying patients with advancing liver disease due to NASH. Further complicating the role of ALT alone, many central laboratories use reference ranges that are significantly above those recommended by liver experts. Major central labs suggest an upper limit of normal for adult males and females at or above 45 IU/L and 30 IU/L respectively. The American College of Gastroenterology (AGA) has recommended that true healthy normal ALT level range is from 29 to 33 IU/L for males, and from 19 to 25 IU/L for females.
In most patients, nonalcoholic fatty liver disease causes no symptoms. Nonalcoholic fatty liver disease often is discovered when routine blood tests show slightly elevated levels of liver enzymes (ALT and AST) in the blood. Another way in which nonalcoholic fatty liver disease is discovered is when ultrasound examination of the abdomen is done for other purposes, say for looking for gallstones, and fat is found in the liver.
Diagnostic goals for NAFLD include identifying those who have a fatty liver and those who are at risk for progressing to cirrhosis. The key is to identify at-risk individuals before they develop either cirrhosis or fibrosis. Several diagnostic tests can determine fatty liver by scans, including computed tomography, magnetic resonance imaging, ultrasound, and the FibroScan CAP score.
To prevent NAFLD from developing into such serious conditions as end-stage liver disease or liver cancer, it is important for clinicians to understand and make use of emerging technologies to identify and engage at-risk patients. Moreover, with the imminent introduction of therapies, NITs are in development and may replace liver biopsy for assessing liver health. With the high prevalence of the disease, NITs combining direct biomarkers, such as those from FibroScan, with blood-based biomarkers are seen as a cost-effective way to assess and monitor patients at risk of advancing disease due to NAFLD in the settings where they receive care.
With this in mind, it is expected that the labs will play a central role as we look to improve patient outcomes, reduce costs, and improve provider satisfaction in managing the complexities of NAFLD and NASH.
Author: Jon Gingrich, CEO, Echosens North America