Dr. Jonathan Riek, VP of Musculoskeletal and Metabolic Imaging at BioTel Research, shares some thoughts, observations and predictions on:
Non-invasive Imaging Tests for NASH
Non-alcoholic steatohepatitis or NASH is the progressive form of fatty liver disease. It is at this stage, that the disease progresses from simple steatosis to more of an inflammatory disease, which leads to lobular inflammation, hepatocellular ballooning, and fibrosis. Conveniently, all of these can be observed on stained histopathology slides from tissue obtained from a biopsy. Because of the invasive nature of the biopsy, the scientific community has been searching for other means to quantify the state of the disease noninvasively.
Two groups are currently planning or running studies to look at non-invasive biomarkers of NASH. The Innovative Medicines Initiative (IMI) in Europe is funding Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) to develop, validate and qualify better biomarkers for testing NAFLD. In the United States, the Foundation for the National Institutes of Health (FNIH) is coordinating Non-Invasive Biomarkers of Metabolic Liver Disease (NIMBLE) to standardize and validate a set of non-invasive biomarkers for the diagnosis and staging of NASH as well as to assess response to therapeutic interventions.
From an imaging standpoint, these groups are looking at MRI and ultrasound technologies to characterize several aspects of the disease including steatosis and fibrosis. Other body composition techniques utilizing Dixon MR imaging can quantify the location and quantity of ectopic fat, visceral fat and subcutaneous fat. There is yet another technique (corrected-T1 or cT1) that claims to be able to measure the amount of hepatic extracellular fluid.
MRI proton-density fat fraction or MRI-PDFF is a technique that accurately quantifies the percentage of hydrogen protons that are visible to MRI that come from lipid molecules as opposed to water molecules. This percentage provides a good indication of the amount of fat in the liver and is likely more sensitive to change than the steatosis component of the NAFLD Activity Score (NAS). This technology was originally published in 2009 and has seen thousands of publications since that time. It is a well validated tool for measuring steatosis.
MR Elastography was first FDA-cleared in 2009 for use on GE scanners. Since that time, it has been cleared for use on Siemens (2012) and Philips (2014). There are currently over 1,000 installed units world-wide and tens of thousands of peer-reviewed publications. MR elastography measures the stiffness of tissues by looking at wave propagation through tissue. Tissue stiffness in the liver is a proxy for liver fibrosis, although there are other factors that can increase liver stiffness, such as inflammation, cysts, and tumors.
T1 relaxation time, or spin-lattice relaxation time, measures the rate at which the hydrogen protons relax back to a steady state after being excited by a radio frequency (RF) pulse. Free water tends to have the longest relaxation times, while bound water has a much shorter relaxation time. Therefore, the more extracellular fluid in the liver, the longer the T1 relaxation time. Increases in extracellular fluid in the liver can be caused by fibrosis, inflammation, and several other factors. The measurement of T1 is influenced by inhomogeneities in the magnetic field, the gradients, and the RF pulse. One contributing factor to the inhomogeneity is iron. Everyone has iron in their liver, but some people have more, and it tends to change the value of T1 that would be estimated if they did not have increased iron. Corrected T1 is a technique that compensates for iron in the liver. Unfortunately, fat in the liver also affects T1, and, depending upon the technique used, it can be substantially increased or decreased based upon the amount of fat. Because a decrease in fat in the liver will cause a decrease in cT1, it may not be the ideal measurement for an anti-steatotic drug trial. The same group that invented iron-corrected T1 (Oxford University) also published a technique to compensate for fat, iron and other sources of inhomogeneity.
Dixon imaging produces two images, one that contains the signal emanating from the water hydrogen protons and one the comes from the lipid hydrogen protons. Using these images, it is relatively straightforward to determine the amount of subcutaneous fat, intramuscular fat, and visceral fat. These measurements can be very relevant for people with metabolic syndrome and fatty liver disease.
There are many other MR imaging techniques that may provide valuable information about the state of the liver. One of these techniques is diffusion-weighted imaging, which measures how water diffuses through tissues. The diffusion is hindered by cell membranes, so this may be another technique that could be useful to quantify extra-cellular fluid.
T2 relaxation time, or spin-spin relaxation time, measures the rate at which the hydrogen protons interact with each other and get out of phase. Similar to T1 relaxation time and diffusion, T2 relaxation time tends to be longest in free water. Also like T1, the measurement of T2 is influenced by iron and fat in the liver.
Contrast-enhanced liver MRI is another imaging technique that can be used to estimate the amount of extracellular fluid by measuring T1 relaxation time before and after contrast administration and combining that with hematocrit levels.
NASH is currently diagnosed and tracked using histopathology, and the measurements that it can provide. By looking at the measurements that MRI can provide, it is possible that some of these measurements may be better at diagnosing or observing change in the state of the disease, even though those measurements may not quantify the exact same measurements in exactly the same way. Here’s hoping that LITMUS, NIMBLE and all the researchers working on non-invasive measurements find a better way.