There is a growing need for non-invasive tests in diagnosing and monitoring treatment of liver fibrosis and cirrhosis, particularly due to fatty liver disease, or non-alcoholic steatohepatitis (NASH). While there are several tests approved for diagnostic use or in development, their accuracy, reliability, and validation in therapeutic clinical trials have yet to be established.
Up to 30 million people in the U.S. suffer from NASH, with up to 9 million of those having advanced fibrosis, including the most severe form, cirrhosis (1). While weight loss (including bariatric surgery) and exercise are helpful in NASH, particularly with early stages of fibrosis, there are no approved medical therapies for any stage of NASH and the only option for NASH cirrhosis is liver transplant.
The medical community is stepping up to meet this hidden epidemic of NASH. According to clinicaltrials.gov, there are 90 open studies focused on NASH, with 27 of them studying various drug treatments. Since it is widely recognized that fibrosis is key in determining patient outcomes from NASH, many of these trials assess liver fibrosis as a trial endpoint.
At this time, the only broadly accepted way to stage liver fibrosis is via a biopsy, an invasive procedure that is fraught with both pain and potentially serious side effects. Additionally, since it only samples 1/50,000th of the liver and there is usually non-uniformity of fibrosis throughout the liver, there are inaccuracies due to sampling variability.
This clinical trial activity, and more to come, represents a major opportunity for us to advance the science surrounding non-invasive testing.
Current and emerging approaches to non-invasive testing in liver fibrosis
There are three basic approaches to non-invasive testing for liver fibrosis: Testing of blood for specific serum biomarkers; the physical assessment of the liver using some form of imaging technology; and finally, the testing of liver function.
Serum tests
This approach has a fundamental problem in that one doesn’t know without rigorous empirical research whether what’s in the serum is reflective of what’s in the liver.
Many individual serum biomarkers, as well as composite scores of multiple biomarkers, have had some success in correlating results to liver fibrosis on biopsy, but they are not very precise. They can tell you whether there’s little fibrosis or a lot of fibrosis, but they can’t tell you all the different gradations in between. There’s no solid evidence that they’re going to be useful in their current iterations for testing the effect of an antifibrotic drug, because such effects are likely to be found in those gradations.
Research using proteomic and metabolomic approaches, circulating micro vesicles and microRNA, and turnover of deuterated proteins is promising, but far from well-defined enough to be used in clinical medicine or efficacy-based clinical trials.
Physical assessment of the liver
A fibrotic liver has very different physical characteristics than a normal liver and some of this can be assessed by external means using diagnostic imaging modalities.
Ultrasound-based transient elastography, as exemplified by the most studied method, FibroScan®, measures the speed of a mechanical pulse as it goes through the tissue, providing a measure of liver stiffness which correlates with liver fibrosis. FibroScan has many desirable characteristics for a test of liver fibrosis in that it assesses an area of liver about 100 times bigger than the area measured by a liver biopsy, is inexpensive, can be done in a provider office setting, is quick, and is painless. Other ultrasound-based tests are available including acoustic radiation force impulse imaging (ARFI) and real-time shear wave elastography (SWE).
Magnetic resonance elastography (MRE) also assesses liver stiffness. MRE has the advantage of evaluating the entire liver, thereby eliminating sampling error of ultrasound-based methods and it simultaneously evaluates the liver for lesions such as tumors. While MRE assessment of liver fibrosis compares favorably to FibroScan, and in some studies is more accurate for staging fibrosis, it requires special equipment added to standard MRI, is much more expensive, and less easily used in a clinical setting.
Software analyses of MRI data (multi-parametric MRI) can measure various tissue parameters such as the amount of fluid, iron, fat and interstitial space in the liver. Since fibrosis and much of the inflammation are found in the interstitial space, this may be a useful test to evaluate how much fibrosis there is in the liver. LiverMultiScan®, one such multi-parametric test approved for diagnostic use in Europe and U.S., shows good correlation with the results of liver biopsies, demonstrated response in a NASH patient after bariatric surgery, and correlates with patient outcomes. LiverMultiScan can evaluate the entire liver, assesses for structural lesions, and is performed on standard MRI equipment without need for special hardware.
Testing of liver function
Because it is difficult to assess liver function, physicians rely on physical assessments like biopsy. Yet there are a number of promising approaches to testing liver function being developed.
One of the functions of the liver is metabolizing drugs and other ingested xenobiotics. A 13C-methacetin breath test developed by Exalenz Bioscience measures the metabolism of a drug. Carbon-13 (13C)-laced methacetin is given to the patient orally, the liver metabolizes the methacetin by knocking off the methyl group, which gets turned into 13C-laced CO2 and exhaled in the breath. Exalenz has shown a correlation between 13C-methacetin metabolic capacity and damage to the liver and patient outcomes in cirrhosis.
One of the functions of the liver is to extract bile acids out of the serum and secrete them into the biliary tree. A company called HepQuant is developing a test for this. A small intravenous dose of a non-radioactive labeled bile acid, as well as an oral dose, is given to the patient and the test measures how well the liver takes up this bile acid. HepQuant has demonstrated a linear correlation between the results of test and various measures of liver disease, such as degree of fibrosis.
As these tests and others like them in development are further refined, they could become important tests in diagnosing and treating liver disease, because they look at not only liver structure, but also at how liver function changes.
Conclusion
Between serum, imaging, and functional tests, there may soon be a wide range of different reliable and non-invasive tests available. Each of these tests measure different things, and it is unlikely that there will be a single test that will be able to give a complete picture of the liver.
Clinical trials are an opportunity not only to test the safety and effectiveness of the drug candidate, but also to test the relevance of selected non-invasive tests. This is something that all companies and academic centers working on treatments for NASH and fatty liver disease should design into their clinical trials. No matter what the results for the candidate drugs, those conducting clinical trials can also gain a better understanding of how the results of non-invasive tests correlate to the results of a liver biopsy, or other invasive tests such as hepatic venous pressure gradient, and disease progression. That would be a tremendous boon to this area of medicine.
Reference List
- Who will be the kings of NASH-ville? Key players and an overview. May 21, 2015, Alethia Young, Deutsche Bank Markets Research
About the Author
Dr. Peter Traber is the President, Chief Executive Officer and Chief Medical Officer of Galectin Therapeutics and adjunct Professor of Medicine at Emory University School of Medicine
Filed Under: Drug Discovery
