Is it time to advance pediatric NAFLD diagnosis to the magnetic resonance imaging era?
Authors: Miriam B. Vos
Journal: Hepatology (2015)

Potential conflict of interest: Dr. Vos received grants from Resonance and Nutrition Science. See Article on Page 1887 In 1910, an article appeared in the Journal of Experimental Medicine by John McCrae and Oskar Klotz entitled "The Distribution of Fat in the Liver."1 The authors examined liver fat quantity, distribution, and appearance in an autopsy series of 100 cases and found in 32 cases "it was considerable in quantity, which condition is probably pathological, for it is attended by an undue friability of the organ." Thus, even in 1910, fatty liver was common and understood as pathologic. Today, the prevalence estimates of nonalcoholic fatty liver disease (NAFLD) are alarmingly high. In the past two decades, NAFLD in children has more than doubled and is now estimated to affect ∼7 million children and 10%‐35% of adults in the United States.2 In 1940, Ralli et al. published the fat content of healthy human livers.4 They point out the following: The great majority of such observations (fatty liver) have been based on the gross and microscopic appearance of the livers. Chemical analysis of the liver gives not only a more exact idea of the total amount of lipid but it is the only means of determining the nature of the lipid changes that may have taken place. Already in 1940 the debate had started: is histopathologic assessment precise enough to determine normal versus abnormal amounts of fat in the liver? The article by Ralli et al. is particularly fascinating because it likely contributed to the definitions that we use today. They demonstrated that a typical piece of healthy human liver tissue contained an average of 4.98 g (range 2.42‐8.41) per 100 g of wet liver. In other words, ∼5% of a healthy liver is fat, a now commonly used reference point. Despite these early concerns regarding microscopic assessment, today's gold standard for the diagnosis of NAFLD remains histopathologic assessment of liver tissue in conjunction with clinical history.5 However, it is a gold standard with recognized flaws. Sampling error exists because of the small size of liver tissue from biopsies and the variability of steatosis location in the liver. For assessment of steatosis, interobserver variability in measurements (κ values) have been reported as high as 0.79 in a highly structured validation study with NAFLD pathology experts.6 While a κ of 0.79 is notable, it remains a subjective gold standard with limited utility as a comparator. A 2012 NAFLD guideline, published in this journal, states that diagnosis of NAFLD requires evidence of steatosis "either by imaging or histology,"7 thereby opening up an opportunity to move away from reliance on liver biopsy. Currently, ultrasound is the most commonly used modality to evaluate hepatic steatosis because of its relatively low cost, availability, and safety. However, similar to liver biopsy, steatosis assessment by ultrasound is subjective and accuracy is operator‐dependent. Furthermore, mild levels of steatosis are often missed because of the limitations of ultrasound.8 Into this environment, Schwimmer et al. have published an article in this issue of Hepatology9 describing a prospective, validation study of magnetic resonance imaging (MRI)–estimated liver proton density fat fraction (PDFF) to measure hepatic steatosis. This is the largest study of this type in children published to date. In brief, the authors used MRI‐estimated liver PDFF to measure hepatic steatosis and compared this to histopathologic grading in 174 children with a mean age of 14 years (range 8‐17). This study has several important findings. All the children completed the MRI acquisition protocol without difficulty. This demonstrates the feasibility of MR‐based steatosis measurements in young children. The correlation of the MRI‐estimated liver PDFF with the pathology assigned steatosis grade was good (0.725). The probability predictions for MRI‐estimated liver PDFF values corresponding to a particular steatosis grade were strong at both the high and low ends of the PDFF spectrum. In other words, very low PDFF values were very likely to predict a steatosis grade of 0 or 1, while very high PDFF values were very likely to have high grades of steatosis. The middle values were less predictive, lowering the overall accuracy of predicting steatosis grade to just 56% (confidence interval 54%‐60%). The examination of diagnostic accuracy between steatosis grade 0 and grade 1 (no disease versus disease) showed stronger results. They utilized four different published proposed thresholds for fat in the liver (1.8%, 5.5%, 6.4%, and 9.0%) and applied these thresholds to the MRI‐estimated liver PDFF data to test the sensitivity and specificity for identifying mild steatosis versus no steatosis. The receiver operating characteristic curves presented demonstrate that none of these cutoffs have the combined sensitivity and specificity desired for a new clinical measure. However, this may be a limitation of the thresholds rather than the MRI‐estimated liver PDFF. The selected thresholds came from four studies using varying MR‐based methodologies and were conducted in adults. In a supplement, Schwimmer et al. provide a post hoc analysis in which they derived and tested an optimal threshold to differentiate steatosis versus no steatosis in children. In their current data set, a cutoff level of 3.5% had 95% sensitivity and 83% specificity, with an area under the receiver operating characteristic of 0.90. Given the already discussed flaws of the "gold standard" liver biopsy, this high level of sensitivity and specificity is promising for the use of MR in diagnosing children with NAFLD, although it will need to be validated in a cohort with both MRI‐estimated liver PDFF and liver histology. There were some limitations to the Schwimmer et al. study which may have contributed to the correlation of 0.725. The width and number of the biopsy cores are not provided, both of which can influence accuracy. Also, a single pathologist graded the specimens a single time. Previous work has shown that assessing each core twice significantly increases the amount of steatosis recorded.10 Finally, the study design resulted in a mean time interval of 57 ± 51 days between the liver biopsy and the MRI. Steatosis can change rapidly, and in the setting of a liver biopsy many parents are motivated to make substantial changes in their child's diet and physical activity. I would argue, however, that their lack of a high correlation is less important. This study is one of hundreds now published in the literature on MRI and NAFLD (a recent PubMed search of keywords "magnetic resonance" and "NAFLD" resulted in 273 articles). The superiority of MR‐based methods (both MRI and magnetic resonance spectroscopy) over ultrasound is clear. The question is, why are we still ordering abdominal ultrasounds to diagnose NAFLD in children? The benefits of MR methods include precision, reproducibility, assessment of a larger area of the liver, and a high level of safety. Barriers that remain include the cost, the requirement for sedation in young children, proprietary measurement protocols, and the fact that there is not a uniform standard for classifying fatty liver by MR. Fortunately, these barriers are resolving. An MR sequence for hepatic fat can be quite brief—as short as 5‐10 minutes compared to 30‐45 minutes required for an abdominal ultrasound. Scheduling brief, focused MR scans could bring down the cost of MR. Gradually, more companies are releasing protocols for hepatic fat measurement, making them available outside of research centers. As the above barriers continue to be overcome, inclusion of MR‐based hepatic fat measurements in the screening, diagnosis, and longitudinal assessment of pediatric NAFLD is becoming possible. While this approach is not viable today for most practitioners, the MRI era is approaching fast.