Normal Liver Stiffness Values in Children Are the Same as in Adults

See also the article by Trout et al in this issue.

Dr Yin is an associate professor in medical physics in the Department of Radiology at the Mayo Clinic. Her research interests focus on distinguishing inflammation, fibrosis, tissue pressure, and tumoral invasiveness with MR elastography technology, advancing diagnostic and prognostic abilities of multiparametric MRI/MR elastography in the liver. Dr Yin serves on NIH study sections and is a principal investigator for two NIH and one Department of Defense grants.

Chronic liver disease is a major global health care challenge that affects both adults and children. There are many causes of repetitive liver injury, including metabolic, infectious, toxic, genetic, and other conditions, leading to hepatic fibrosis and liver failure. The presence and severity of liver fibrosis are some of the most important prognostic factors determining long-term outcomes in chronic liver disease (1,2). Liver biopsy has served as the reference standard for assessing hepatic fibrosis. However, it has many disadvantages, including invasiveness, high cost, sampling error, and subjective histopathologic interpretation. The limitations of biopsy have motivated efforts to develop safer, less expensive, noninvasive methods for reliably detecting and staging liver fibrosis. This need is especially apparent in pediatric medicine.

Over the last decade, MR elastography has emerged as a reliable method in detecting and assessing liver fibrosis. Multiple publications have documented an emerging consensus that liver stiffness measurement assessed at MR elastography provides the highest diagnostic performance and lowest technical failure rate in detecting and staging liver fibrosis, compared with other imaging-based technologies, including US-based elastography (3).

Normal liver tissue is soft, similar to subcutaneous fat in stiffness. With fibrosis, the accumulation of collagen in the extracellular matrix causes the stiffness of liver tissue to increase systematically. In advanced fibrosis (stage 4), the liver stiffness may increase by 400% (4). However, the change associated with mild and moderate fibrosis is smaller, on the order of 20%–50%.

To establish threshold values for liver stiffness that can separate the healthy from the fibrotic liver, it is critical to define the normal range of liver stiffness with MR elastography. Accordingly, multiple published studies have indicated that the liver stiffness (defined as the magnitude of the complex shear modulus at 60 Hz) assessed at MR elastography in healthy adults is clustered around a mean value in the range of 1.9–2.2 kPa. The preponderance of evidence also indicates that this normal range in adults is not substantially affected by age, sex, hepatic steatosis, or body mass index.

But many clinical markers have different normal ranges in children. Is liver stiffness one of them? To date, the literature has not been conclusive. In this issue of Radiology, Trout et al (5) established the normal range of liver stiffness in healthy children as measured at MR elastography by using both 1.5-T and 3.0-T MRI systems from three major vendors (GE, Siemens, and Philips). This well-designed and carefully executed study shows that liver stiffness assessed at MR elastography in healthy children is similar to that of adults, with a mean value of 2.1 kPa. No evidence was shown that sex, age, or body mass index had an effect on liver stiffness measurements across imager vendor and field strength. These results provide preliminary normative values for pediatric clinical practice for early screening and timely intervention. The work is an important milestone in making progress in identifying optimal diagnostic thresholds for pediatric fibrosis staging.

What is next? Many of the pathophysiologic changes including inflammation, congestion, fibrosis, and portal hypertension lead to elevation in the liver stiffness measurement (3). Recent advances in MR elastography that acquire multiple mechanical properties can more comprehensively help characterize hepatic inflammation and fibrosis. Investigators have combined the multiparametric MR elastography with proton density fat fraction assessed at MRI. This combination shows high accuracy in diagnosing nonalcoholic steatohepatitis and in predicting the nonalcoholic fatty liver disease (NAFLD) activity score (unweighted sum of histologic gradings of steatosis, inflammation, and ballooning) in both preclinical models and clinical patients (6,7). With a growing epidemic of obesity worldwide, a guideline focused primarily on diagnosis and management of pediatric NAFLD was released in 2017 (8). In this guideline, the inexpensive liver function tests are preferred as the first-line screening test despite their limitations. When available, MRI or MR spectroscopy is highly recommended to depict and help quantify steatosis extent for diagnosing and monitoring NAFLD. It is logical to employ a streamlined MRI protocol that combines MRI and MR spectroscopy with MR elastography to comprehensively screen abnormal changes of the liver in children. We have a poor understanding of the burden of NAFLD in children, including environmental and genetic risk factors. This lack of understanding has ramifications for public health initiatives, which include developing optimal screening guidelines and designing effective health care policy in children. The study by Trout et al will facilitate the future application of streamlined MRI and MR elastography imaging to provide a comprehensive quantitative assessment of liver health in children.

As pointed out by Trout et al, their study did not assess liver stiffness in children younger than 7 years. It remains to be determined whether the normal values already established will apply to younger children. Future translation of child-appropriate free-breathing methods into MR elastography may help to fill this knowledge gap and, most importantly, to improve patient experience in general. A recent pilot study (9) has shown that the averaged liver stiffness as measured by a four-slice two-dimensional free-breathing MR elastography method agreed well with the standard breath-held MR elastography. To evaluate the entire organ, a self-navigated, motion-resolved, three-dimensional free-breathing MR elastography examination can be implemented with a hybrid radial echo-planar-imaging readout scheme and compressed sensing type of reconstruction (10). Could an improved understanding of the natural evolvement of liver stiffness over the entire life span lead to new guidelines? Could other MR elastography–assessed biomechanical properties (eg, viscosity, porosity, nonlinearity, and tissue pressure) provide a way to discriminate and individually quantify different parts of the disease processes (eg, inflammation, fibrosis, and cell injury) in the liver? Only further research will tell.