Liver fat quantification: where do we stand?

Abstract

Excessive intracellular accumulation of triglycerides in the liver, or hepatic steatosis, is a highly prevalent condition affecting approximately one billion people worldwide. In the absence of secondary cause, the term nonalcoholic fatty liver disease (NAFLD) is used. Hepatic steatosis may progress into nonalcoholic steatohepatitis, the more aggressive form of NAFLD, associated with hepatic complications such as fibrosis, liver failure and hepatocellular carcinoma. Hepatic steatosis is associated with metabolic syndrome, cardiovascular disease and represents an independent risk factor for type 2 diabetes, cardiovascular disease and malignancy. Percutaneous liver biopsy is the current reference standard for NAFLD assessment; however, it is an invasive procedure associated with complications and suffers from high sampling variability, impractical for clinical routine and drug efficiency studies. Therefore, noninvasive imaging methods are increasingly used for the diagnosis and monitoring of NAFLD. Among the methods quantifying liver fat, chemical-shift-encoded MRI (CSE-MRI)-based proton density fat-fraction (PDFF) has shown the most promise. MRI-PDFF is increasingly accepted as quantitative imaging biomarker of liver fat that is transforming daily clinical practice and influencing the development of new treatments for NAFLD. Furthermore, CT is an important imaging method for detection of incidental steatosis, and the practical advantages of quantitative ultrasound hold great promise for the future. Understanding the disease burden of NAFLD and the role of imaging may initiate important interventions aimed at avoiding the hepatic and extrahepatic complications of NAFLD. This article reviews clinical burden of NAFLD, and the role of noninvasive imaging techniques for quantification of liver fat.

Keywords: Hepatic steatosis; Liver fat quantification; Magnetic resonance imaging; NAFLD; NASH; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; Noninvasive quantitative biomarker.

Fig. 1

Conventional ultrasound (US) can detect liver fat droplets through increased scattering, which leads to increased liver parenchyma echogenicity, and through increased attenuation, which leads to blurring and poor visualization of deep structures. Shown are four examples of patients with liver fat ranging from normal (a) to increasingly severe hepatic steatosis (b-d). Arrows depict increased obscuration of the diaphragm with increasing severity of steatosis. Note decreased visualization of vessels and bile ducts with increasing liver fat content.

Fig. 2

Triglycerides have lower X-ray attenuation than normal liver parenchyma, leading to decreased CT attenuation with increasing liver fat content. Shown are four examples of patients with varying degrees of liver fat content assessed by non-contrast CT. Using CT, the degree of hepatic steatosis can be quantified using the absolute CT attenuation of liver parenchyma (Hounsfield units) or by the relative attenuation difference between liver parenchyma and spleen. Examples include a normal liver (a) and patients with moderate (b), severe (c) and extreme (d) hepatic steatosis. HU, Hounsfield Unit. Decreased x-ray attenuation on non-contrast CT correlates closely and linearly with MRI-PDFF [41]. The MRI-PDFF equivalents to 65 HU, 35 HU, 12 HU and −8 HU are approximately 0.5%, 28%, 31% and 43%, respectively.

Fig. 3

Factors that increase the X-ray attenuation of liver on CT will confound the ability of CT to quantify liver fat due to increased liver density, potentially masking the presence of fat which lowers tissue attenuation. As an example, CT images demonstrate effects of amiodarone (b) and severe iron overload (c) in two patients. In comparison to the patient with normal liver (a), amiodaron and iron increase liver attenuation (b, c) in similar way as hepatic steatosis. Thus, in the presence of amiodaron or iron a concomitant hepatic steatosis could be neither confirmed nor exclude using CT. Note, that due to an increased attenuation of the liver parenchyma liver vessels (depicted by arrows on image b and c) appear hypodense to the parenchyma.

Fig. 4

Longstanding hepatic steatosis can lead to NASH-related cirrhosis. As shown in this 55-year-old patient, severe steatosis (a) was noted 12 years earlier on a CT performed primarily to exclude pulmonary embolism. Follow-up CT showed progression into cirrhosis (b) with liver atrophy and surface nodularity depict by arrows).

Fig. 5

MR spectroscopy (MRS) can provide confounder-corrected estimates of proton density fat-fraction (PDFF), typically within a single voxel [63]. Axial T2-weighted scout MR image (a) demonstrates the correct placement of the of the MRS voxel (white square), placed in the right lobe of the liver avoiding large vessels, lesions, bile ducts and the liver edge. Figure b shows an example (STEAM) MR spectrum in patient with mild steatosis, acquired at multiple echo times, demonstrating the presence of both water and fat peaks. Post-processing can be used to correct for the effects of T2 signal decay and the multi-peak spectral characteristics of fat.

Fig. 6

Chemical shift encoded MRI (CSE-MRI) can quantify PDFF as a quantitative biomarker of liver fat content, across the entire liver within a single breath-hold. Shown are representative examples of complex-based CSE-MRI parametric PDFF maps of 3 children. The entire liver was evaluated within only a single 20s breath-hold. PDFF values of the first patient (age 11, male) showed minimal fat content in the liver (normal <6%). PDFF values of the second and third patient (age 11 and 12, male) revealed medium amount of liver fat, consistent with hepatic steatosis in young age.

Fig. 7

CSE-MRI enables simultaneous estimation of liver fat- and iron concentration. Using confounder-corrected R2* (1/T2*), the R2* maps are reconstructed from the same CSE-MRI acquisition data as PDFF maps. The R2* is quantitative biomarker of iron concentration, clinically relevant in patients who suffer from concomitant NAFLD and iron overload. Coexisting fat and iron deposition in the liver can be also present in viral hepatitis, HCC, hemosiderosis and hemochromatosis. As shown, Patient 1 had high fat but normal iron content in the liver, while patient 2 has both, severe hepatic steatosis and hepatic iron overload. Patient 3 had extreme high iron deposition in the liver due to hemochromatosis, however normal fat content.

Fig. 8

Among the non-invasive modalities used for quantification of liver fat, MRI-PDFF is the most accurate technique for the evaluation of liver fat content. Shown is an example of conventional ultrasound image (a), CT image (b) CSE-MRI with PDFF map (c) of 41-year-old male patient with severe hepatic steatosis. The US beam is attenuated by liver fat, resulting in decreased beam penetration; therefore, structures in liver parenchyma, such as blood vessels (star), and diaphragmatic outline (arrow) are obscured.