Only a doctor can diagnose a liver disease and it is complex, but if you as a patient are better informed, your ability to understand the diagnosis and to ask the right questions will enable you to have a better dialog with your doctor. Learning about the tools (besides biopsy) that you can use to monitor the progress of your fatty liver disease will better prepare yourself to engage with your physician. These tools are not widely known, so who knows, you might even teach your physician something new!

Noninvasive testing options are a fantastic development in the study and care of fatty liver disease. Though the “gold standard” for diagnosis is still a liver biopsy, there are many alternative testing options that are not as expensive, risky, or uncomfortable. Whether you are trying to determine if you are a candidate for a biopsy or you have already been diagnosed, these tests can be informative. After all, the more information you have about your disease, the better you’ll be able to fight it.

There are two main types of noninvasive tests: blood-based and imaging-based. Blood-based tests are more widely available, because all they require is a simple blood draw. They may also be called “biomarker” tests, which is just another way of saying labs will be looking for certain compounds in your blood that indicate different things. Imaging-based tests are less widely available, but if you can find them, they may help paint a more vivid picture of what is going on in your body. Imaging-based tests are often done with ultrasound or MRI devices equipped with specialized liver software.

Examples of blood-based tests

FIB-4 Index

What it measures: fibrosis

Who should take it: anyone concerned about their liver

Where to get it: primary care provider, online calculator

The FIB-4 Index is a blood-based test that looks at underlying fibrosis that can be used as a measure to help determine NAFLD/NASH status. While originally developed to detect liver fibrosis among patients with Hepatitis C and HIV, FIB-4 scoring has been increasingly used by the diabetes and NAFLD/NASH communities. [1] [2] [3] The FIB-4 scoring system is determined from the values of patient age, platelet count, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Because all of these tests are available to primary care physicians, FIB-4 is a highly accessible and affordable screening tool.

In clinical trials for NAFLD/NASH diagnosis, patients with a FIB-4 score <1.3 were classified as not having advanced fibrosis, while patients with a FIB-4 score >2.67 were classified as having advanced fibrosis.[4] Those with FIB-4 scores 1.3-2.6 were indeterminate, requiring further testing. As a test to rule out advanced fibrosis (FIB-4 <1.3), FIB-4 has a negative predictive value of 90-95%. This means that 90-95% of those identified as not having advanced fibrosis truly do not have advanced fibrosis, while the remaining 5-10% are false negatives requiring further validation. As a test to rule in advanced fibrosis (FIB-4 >2.6), FIB-4 has a positive predictive value of 80%. This means that 80% of those identified as having advanced fibrosis truly have advanced fibrosis, while the remaining 20% are false positives requiring further validation.

Unlike some other tests, FIB-4 looks solely at fibrosis, not taking into consideration other factors important for diagnosis and monitoring of NAFLD/NASH such as steatosis and activity. While it is fairly limited in this sense, the high accuracy in detection of fibrosis makes it a strong starting point for NAFLD/NASH diagnosis that can help the right patients get on track for further testing and treatment. As all of these tests are readily available to primary care physicians, FIB-4 is a highly accessible and affordable screening tool. If you have your platelet count, AST, and ALT values from a previous bloodwork, you can enter them yourself into online calculators, such as this one.

[1] Sterling et al., Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection, Hepatology, June 2006, doi: 10.1002/hep.21178.

[2] Filozof et al., Liver Fibrosis as Assessed by the FIB-4 Index in Patients with Type 2 Diabetes (T2DM), Diabetes, July 2018, doi: 10.2337/db18-1570-P.

[3] Shah et al., USE OF THE FIB4 INDEX FOR NON-INVASIVE EVALUATION OF FIBROSIS IN NONALCHOLIC FATTY LIVER DISEASE, Clinical Gastroenterology and Hepatology, October 2009, doi: 10.1016/j.cgh.2009.05.033.

[4] Alkhouri and McCullough, Noninvasive Diagnostics of NASH and Liver Fibrosis Within the Spectrum of NAFLD, Gastroenterology & Hepatology, October 2012.

Enhanced Liver Fibrosis (ELF) Panel

What it measures: fibrosis

Who should take it: diagnosed NAFLD/NASH patients

Where to get it: Europe

The Enhanced Liver Fibrosis (ELF) panel, is a blood test developed by Siemens Healthineers that measures fibrosis using serum markers. Though this test is not commercially available in the United States, ELF is typically used to assess the risk of progression to cirrhosis and liver-related clinical events, most commonly to diagnose advanced fibrosis, ≥F2, in patients with NAFLD/NASH. [1]

The ELF test is a panel of three biomarkers: type III procollagen peptide (PIIINP), hyaluronic acid (HA), and tissue inhibitor of metalloproteinase-1 (TIMP1). These values are summarized into a single score, which can be compared to different thresholds for diagnosis. The thresholds recommended by Siemens are 7.7 (lower threshold) and 9.8 (higher threshold). Meta-analysis has shown that the lower threshold of 7.7 had a sensitivity of 0.93 and a specificity of 0.34; this means that 93% with advanced fibrosis will be identified, while 34% of those without advanced fibrosis will be identified. [2] The higher threshold of 9.8 showed a specificity of 0.86 and a sensitivity of 0.65; this means that 86% of those with advanced fibrosis will be identified, while 65% of those without advanced fibrosis will be identified. As you can see, the lower threshold ensures that more people with advanced fibrosis will be accurately identified, at the expense of accurately identifying those without advanced fibrosis.

Interestingly, the National Institute for Health Care and Excellence (NICE), a guideline-publishing public health body in England, sets the threshold for ELF at 10.51. At this value, ELF demonstrates a specificity of 0.93 and sensitivity of 0.51. [3] In other words, a cutoff of 10.51 means that 93% of those with advanced fibrosis will be identified and 51% of those without advanced fibrosis will be identified.

While it is important to consider the effects of these various thresholds, the prevalence of advanced fibrosis in a population also has a significant impact. How much advanced fibrosis is present in a population determines which threshold should be used. In settings with a low prevalence, ELF is a useful tool to rule out NAFLD/NASH patients from having advanced fibrosis and less certain when trying to rule in advanced cirrhosis. At a prevalence >30%, the ability of the test to accurately identify those with advanced cirrhosis is much lower. [4]

[1] Vali, Yasmin et al., Enhanced liver fibrosis test for the non-invasive diagnosis of fibrosis in patients with NAFLD: A systematic review and meta-analysis, Journal of Hepatology, April 2020, doi: https://doi.org/10.1016/j.jhep.2020.03.036

[2] Vali et al.

[3] Vali et al.

[4] Vali et al.

LIVERFASt

​​What it measures: steatosis, activity, fibrosis

Who should take this: anyone concerned about their liver, diagnosed NAFLD/NASH patients

Where to get it: we are working with Fibronostics to make this available to our members again

LIVERFASt is a blood-based test developed by Fibronostics that looks at steatosis, activity, and fibrosis using an algorithm to analyze 10 distinct biomarkers. LIVERFASt measures the presence and extent of steatosis (fattiness), activity (inflammation and ballooning), and fibrosis (scarring) to determine level of NAFLD/NASH. [1] The algorithm is key to LIVERFASt and has been trained and tested on thousands of patient cases around the world. [2] [3] Once a lab draws blood and assesses the 10 biomarkers, the results can be inputted into the LIVERFASt online portal, which uses the algorithm to calculate scores. The use of the algorithm helps improve consistency in results, which has proven to be a challenge for human pathologists. The algorithm analyzes the biomarker results, assigning patients a score for fibrosis, activity, and steatosis.

These scores, in combination with demographic information (age and gender), are used to classify patients into different levels of NAFLD/NASH as follows:

• NAFLD, only: fibrosis stage is 0, activity stage is <2, steatosis stage is 0

• NAFLD or initial NASH: fibrosis stage is 0, activity stage is 2, steatosis stage is 0

• Moderate NASH: fibrosis stage is 1 or 2, activity stage is >2, steatosis stage is >0

• Advanced NASH: fibrosis stage is 3 or 4, activity stage is >2, steatosis stage is >0

The ability of the LIVERFASt test to distinguish between levels of severity of NAFLD and NASH addresses one of the more challenging aspects of diagnosis. With its user-friendly results and graphics (shown in the first image), LIVERFASt allows this information to be obtained simply and affordably enough to encourage regular retesting and restaging. The accessibility of this technology has the potential to improve disease management and understanding of progress in a manner both attainable for and accessible to patients and providers.

[1] Aravind et al., Machine Learning Technology for Evaluation of Liver Fibrosis, Inflammation Activity and Steatosis (LIVERFAST), Journal of Intelligent Learning Systems and Applications, April 2020, doi: 10.4236/jilsa.2020.122003

[2] Aravind et al.

[3] Tangvoraphonkchai et al., Comparative assessment liver lesions using non-invasive serum biomarkers LIVERFAStTM , FIB4, APRI and liver stiffness measurement (LSM, Fibroscan) in chronic hepatitis C (CHC) patients with liver biopsy, Fibronostics, September 2020.

Examples of imaging-based tests

FibroScan

What it measures: fibrosis, steatosis

Who should take it: undiagnosed and diagnosed NAFLD/NASH patients

Where to get it: specialty care centers, hospitals, some primary care providers

FibroScan is an imaging-based test developed by Echosens that looks at liver fibrosis (stiffness, scarring) and steatosis (fat) using transient-elastography technology. FibroScan can be used on patients in need of staging of their NAFLD/NASH, whether their condition is suspected or biopsy-confirmed. FibroScan works similarly to an ultrasound, emitting a small pulse of energy, called a shear wave. The speed of the shear wave is measured as it travels through your liver, generating two scores to determine overall liver health. The first score measures liver stiffness and the second score measures liver fat. In combination, these scores can help you understand your overall liver health and how it may change over time with lifestyle or medical interventions. [1] The only thing you will feel while taking the test is a light vibration on your skin and the entire procedure takes less than 10 minutes.

Depending on where you get a FibroScan may determine the scoring system used in your diagnosis. Typically, a 5-point scoring system is used to grade the degree of liver fibrosis, from F0-F4. Scores from the FibroScan will be in kilopascals (kPa), ranging from 2 to 75 kPa. Normal livers fall between 2 and 6 kPa, with anything outside this range indicating some degree of liver disease. [2] The table below, adopted from MSK, considers different scores in the context of different liver diseases and can be used to help determine fibrosis score. It is important to remember that the ranges in the table are estimates, and your actual fibrosis score may not match what the table says. When determining your actual fibrosis score, in addition to your fibrosis measurement, your provider will take into consideration your health history and the grade of steatosis.

To use the table, find the liver disease that you have on the left side of the table. Read across the row from left to right until you find the range that includes your fibrosis result. Then, look at the top of that column to see the fibrosis score. [3]

FibroScan has been in available in the European market since 2003 and was expanded to China, Canada, Brazil, Japan, and many other countries before being approved by the FDA in 2013.[4] It is reimbursable by insurance. To find a location near you with a FibroScan machine, use Echosens’ locator, which can be found here.

[1] Echosens, For Patients, https://echosens.us/for-patients/

[2] Memorial Sloan Kettering Cancer Center, Understanding Your FibroScan Results, February 2018, https://www.mskcc.org/cancer-care/patient-education/understanding-your-fibroscan-results

[3] Memorial Sloan Kettering Cancer Center

[4] Echosens, FDA Approves FibroScan® for Non-invasive Liver Diagnosis, April 2013, https://www.prnewswire.com/news-releases/fda-approves-fibroscan-for-non-invasive-liver-diagnosis-203186961.html#:~:text=%2D%20Echosens%E2%84%A2%20is%20pleased%20to,technology%20in%20the%20United%20States.

Velacur

What it measures: fibrosis, steatosis

Who should take it: undiagnosed and diagnosed NAFLD/NASH patients

Where to get it: certain primary care providers, specialty centers, and hospitals; clinical trials 

Velacur is an imaging-based test developed by SonicIncytes that looks at liver fibrosis (stiffness, scarring) and steatosis (fat) using ultrasound technology. Velacur can be used to help diagnose and monitor NAFLD/NASH and is a quick and comfortable procedure. Velacur uses technology similar to MRI elastography, using multiple frequency steady-state waves to generate a 3D liver tissue sampling.[1] The images produced are enhanced by machine-learning and multiple clinical studies have demonstrated consistently high correlation to MRI for measuring steatosis and fibrosis.[2]

Your physician or a trained technician perform the procedure on you while you are lying down, placing a gently vibrating pad under the right side of your back and running an ultrasound probe over your ribs to scan your liver. The entire process takes only about 5 minutes and results are immediately available.[3]

Results from a Velacur reading can be seen in the image below. The two main results from the scan are elasticity and attenuation. Elasticity is a measure of fibrosis and attenuation is a measure of steatosis. Together, these scores will allow your provider to diagnose and monitor the severity of your NAFLD/NASH.

In comparison to transient or ultrasound elastography, Velacur’s advantages are deeper tissue measurement, larger tissue sampling, 3D data acquisition, using a single probe for all body types, fewer user readings required, machine-learning enhanced image guidance, and greater comfort.[4] In comparison to other tools, Vealcur is the most cost-effective and has the advantage of not requiring pre-approval from insurance.[5]

[1] SonicIncytes, Products, https://www.sonicincytes.com/products/

[2] SonicIncytes, Products, https://www.sonicincytes.com/products/

[3] SonicIncytes, Patient Brochure, https://sonicincytes.com/wp-content/uploads/2020/12/SI_VelacurBrochure_WEB.pdf

[4] SonicIncytes, Technology, https://www.sonicincytes.com/technology/

[5] SonicIncytes, Products, https://www.sonicincytes.com/products/

LiverMultiScan

What it measures: fibrosis, steatosis, activity, iron

Who should take it: undiagnosed and diagnosed NAFLD/NASH patients

Where to get it: medical centers with MRI machines and the software 

LiverMutiScan (LMS) is an imaging-based test developed by Perspectum that uses multiparametric MRI to look at liver activity, fibrosis, steatosis, and iron levels. The results are in the form of three reports: cT1, T2*, and PDFF. Scans take about 15 minutes in an MRI machine and require no contrast injections. Images acquired at sites are analyzed by teams at Perspectum Diagnostics using proprietary algorithms to generate an easy to interpret report. 

cT1, or corrected T1, is a metric that corresponds to activity (inflammation) and fibrosis. In comparison to T1, cT1 is more reliable as it accounts for the level of iron in the liver, which can interfere with MRI measurement and lead to underestimation of disease. 

Example cT1 images shown indicate how cT1 depends on fibrosis and activity in patients without high levels of steatosis. Normal range of 633 to 749 ms derived from 95% confidence interval of the distribution of cT1 values in healthy subjects with BMI <25kg/m2 and liver fat <5%. [1] 

T2 is a biomarker that measures the amount of iron in the liver. This measurement is the value cT1 uses to adjust for levels of liver iron that could interfere with MRI results. Tissues with high iron typically have very low T2, while tissues with low iron have higher T2 values. In addition to being used in the cT1 measurement, T2 is clinically important on its own. The ability to detect and monitor the treatment of high iron levels can help patients and doctors manage the condition and reduce the impact of high iron on progression to advanced liver disease. [2]

PDFF, or proton density fat fraction, is a fundamental MRI measurement that quantifies the amount of fat in tissue. Specifically, LMS uses the IDEAL (Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation) measurement, which accounts for the impact on the MRI signal of iron in the liver and the multi-spectral nature of liver fat and is IP licensed from the University of Wisconsin.

Example LMS IDEAL PDFF images show different levels of liver fat, with the normal range of <5.6% based on literature values calculated from general population data. [3]

Though LMS is not yet widely available in the US, it is a promising tool for diagnosing and monitoring NAFLD/NASH. Because it includes measurements for fibrosis, steatosis, activity, and iron levels in the liver, it provides one of the most comprehensive non-invasive pictures of liver health available on the market today. That being said, it is not meant to be used as the only metric in diagnosis, but rather in conjunction with liver function tests, blood tests, ultrasound scanning, and liver biopsy at the discretion of a qualified clinician. [4]

[1] Perspectum, Understanding cT1. https://perspectum.com/media/2081/mkt0073-ct1-explainer-40.pdf

[2] Perspectum, Understanding T2*. https://perspectum.com/media/2084/mkt0091-t2star-explainer-20.pdf 

[3] Perspectum, Understanding PDFF. https://perspectum.com/media/2083/mkt0089-pdff-explainer-20.pdf

[4] Perspectum, A Guide to Interpreting Liver Tissue Characterisation for Clinicians. https://perspectum.com/media/1736/002-a-guide-to-interpreting-liver-tissue-characterisation-for-clinicians-pdm135-80.pdf