Ultrasound Derived Fat Fraction (UDFF)

White paper Ultrasound Derived Fat Fraction (UDFF) Michele Baillie, B.Sc, RDMS, RDCS Siemens Medical Solutions USA Inc., Ultrasound Business Area Issaquah, Washington Aaron Jay Engel, PhD Siemens Medical Solutions USA Inc., Ultrasound Business Area Issaquah, Washington Arati Gurung, PhD Siemens Medical Solutions USA Inc., Ultrasound Business Area Issaquah, Washington siemens-healthineers.com/ultrasound SIEMENS Healthineers White paper · Ultrasound Derived Fat Fraction (UDFF) Introduction Fatty liver occurs when an excess amount of fat builds up The second, nonalcoholic steatohepatitis or NASH, is in the liver. A liver is considered “fatty” if the amount of the more progressive form of NAFLD that can lead to fat contained within the hepatocytes is greater than 5%.1 greater health issues over time.3 Major contributing Fatty liver, or steatosis, is a broad term that encompasses factors to NASH are thought to be metabolic (i.e., insulin two distinct categories of liver disease; alcoholic fatty resistance, diabetes), dietary, and obesity (Figure 1). liver disease (AFLD), which results from excessive alcohol use, and nonalcoholic fatty liver disease (NAFLD), which Simple steatosis has little to no symptoms leaving stems from factors outside of alcohol use. Of these two many patients to go undiagnosed. Left untreated, these categories, nonalcoholic fatty liver disease is considered patients can progress to a more serious disease state and the most common chronic adult liver disease worldwide are only diagnosed when more prominent symptoms affecting over 25% – or 1 billion – people.2 arise, such as abdominal pain, bloating, or even jaundice. Early assessment and characterization of liver steatosis There are two disease state classifications of NAFLD. The while still in the initial reversible stage is key to overall first, simple steatosis, is the initial and reversible fatty disease management and improved patient outcomes. liver state. 2 siemens-healthineers.com/ultrasound Ultrasound Derived Fat Fraction (UDFF) · White paper Obesity / overweight Metabolic syndrome Insulin resistance DXDXT NASH High cholesterol Diabetes Risk factors Medications Hypothyroidism Fatty diet Figure 1: While the exact cause of NASH is not truly known, the disease is known to be rooted in fatty infiltration of the liver. Fatty liver, and therefore NASH, has a broad etiological spectrum that can involve metabolic disorders, certain medications, body habitus size, and even lifestyle choices, such as a fatty diet. Metabolic syndrome, which is a combination of several of the above factors, also increases the likelihood of a person developing NASH. Current methods for the detection of fatty liver disease to aid clinicians in determining hepatic steatosis. involves either an invasive liver biopsy or costly MRI-PDFF and UDFF methods classify hepatic steatosis noninvasive magnetic resonance imaging (MRI) tests as an index value greater than 5%. With the use of this which are not widely available. There is a significant simple tool, physicians now have a new, noninvasive way need for a noninvasive and easily performed testing to help manage adult patients** with hepatic steatosis. method to help diagnose these patients. Ultrasound Derived Fat Fraction (UDFF) is a new and innovative advanced application available for use on the ACUSON Sequoia ultrasound system. UDFF can quantify the amount of fat contained within a patient’s liver quickly and painlessly in just seconds* during a routine abdominal ultrasound. UDFF delivers a similar clinical utility to MRI Proton Density Fat Fraction (MRI-PDFF) * Based on 5 UDFF acquisitions when used as a stand-alone feature. ** When used as part of an overall assessment of hepatic steatosis. siemens-healthineers.com/ultrasound 3 White paper · Ultrasound Derived Fat Fraction (UDFF) Fatty Liver Disease What is a fatty liver? Fatty liver, known as steatosis, is the abnormal and fat in the diet. In most cases people have no symptoms, excessive accumulation of fat globules in the hepatocytes as having a simple fatty liver does not cause any of the liver. Histologically, a normal, healthy liver immediate harm or prevent the liver from functioning contains up to 5% fat in its hepatocytes. Should this fat normally. Over time however, there is concern. Prolonged level climb beyond the 5% threshold the liver is then and continuous fat build-up within the hepatocytes classified as being “fatty” (Figure 2).5 creates a cycle of constant injury and repair within the Fatty liver occurs when fat molecules are not metabolized liver. This persistent cycle paves the way to more serious efficiently enough by the body and end up stored in the and permanent liver conditions and what was once liver. The pathophysiology of insufficient fat metabolism a reversible state of simple steatosis can progress to can be linked to many different factors such as metabolic inflammation (steatohepatitis), fibrosis (scarring), and conditions, medications, or even the overconsumption of eventually, cirrhosis and/or liver failure. 4 siemens-healthineers.com/ultrasound Ultrasound Derived Fat Fraction (UDFF) · White paper Normal/healthy liver Fatty liver Figure 2: Normal healthy liver tissue compared to fatty liver at a cellular level. Normal liver tissue consists of healthy hepatocytes surrounded by blood vessels and portal triads. In a fatty liver, these hepatocytes become filled with excess fat globules. These globules are stored in the hepatocytes when the body cannot keep up to the metabolic pace that the amount of fat present demands. Histologically, liver fat is graded from 0 to 3 based on hepatocyte fat content. Grade 0 (normal) = < 5%, grade 1 (mild) = 5%–33%, grade 2 (moderate) = 34%–66%, and grade 3 (severe) = ≥ 67%.6 The liver is considered fatty when more than 5% of hepatocytes contain fat. Nonalcoholic Fatty Liver Disease (NAFLD) There are two types of fatty liver disease. Alcoholic fatty • Metabolic conditions, such as those associated with liver disease (AFLD), which results from excess alcohol insulin resistance or high cholesterol7 consumption, and Nonalcoholic fatty liver disease • (NAFLD), which is not attributed to alcohol use. Of the Those with diabetes and hypothyroidism are also at two conditions, NAFLD is currently the most common increased risk7 cause of chronic liver disease worldwide.3 The exact • Certain prescription medications or steroids7 cause of NAFLD is not truly known, however it is thought • to be associated with a wide range of diseases and A body habitus that is overweight or obese7 conditions that increase the risk of someone developing Nonalcoholic fatty liver disease is further divided into NAFLD. These include, but are not limited to: two categories each with a different associated risk. The first, nonalcoholic fatty liver (NAFL) is a simple and reversible fatty infiltration of the liver. NAFL is considered siemens-healthineers.com/ultrasound 5 White paper · Ultrasound Derived Fat Fraction (UDFF) Fatty liver disease 2 classifications Alcoholic fatty liver disease (AFLD) Nonalcoholic fatty liver disease (NAFLD) 2 categories Nonalcoholic fatty liver (NAFL) Nonalcoholic steatohepatitis (NASH) • Simple steatosis • Greater fat accumulation • Reversible • Inflammation, constant damage • Considered benign and repair of liver cells, scar tissue • Minimal risk of progression • Progressive – can lead to cirrhosis and/or liver failure Figure 3: There are two classifications of fatty liver disease based on the causative factors. Alcoholic fatty liver disease (AFLD) is fatty liver disease that results from the excessive use of alcohol. Nonalcoholic fatty liver disease (NAFLD) results from factors outside of alcohol use which include medication use, metabolic disorders, and obesity to name a few. NAFLD has two categories or stages of disease. The initial benign stage, nonalcoholic fatty liver (NAFL), or the more progressive stage of nonalcoholic steatohepatitis (NASH). NAFL can be a precursor to NASH if left untreated. a benign condition, as it is thought to have minimal risk This inflammatory stage is known as steatohepatitis. of progression to cirrhosis if diagnosed early and the Sustained inflammation causes cellular damage within necessary steps are taken to reverse the condition.3 Left the liver, as the cells are in a constant state of injury untreated NAFL can, over time, become the precursor and repair. Eventually this constant attempt to repair that leads to the second, and more progressive disease and replace damaged cells leads to the formation of scar state of NAFLD known as Nonalcoholic steatohepatitis, tissue (fibrosis). If the amount of scar tissue becomes or NASH. When compared to NAFL, NASH is thought severe enough, it begins to impair liver function; when to have a significantly increased risk of progression to liver function becomes extremely impaired, cirrhosis cirrhosis and/or end stage liver failure (Figure 3). NASH results. Cirrhosis is an irreversible condition and carries results when there is an even greater accumulation of an increased risk of developing liver failure and/or fat within the liver tissue ultimately resulting in fibrotic liver cancer. While not every individual will progress changes. It has few or no outward symptoms initially to cirrhosis or liver cancer, early assessment and and often goes undiagnosed until it has progressed to characterization of liver steatosis is essential to help a more advanced state. NASH begins when the excess implement treatment or intervention to lower risk fat acts as a toxin and causes inflammation of the liver. and curb advancement of NAFL to NAFLD (Figure 4). 6 siemens-healthineers.com/ultrasound Ultrasound Derived Fat Fraction (UDFF) · White paper NAFL NASH Normal liver Steatosis Inflammation Early fibrosis Significant Cirrhosis Cirrhosis (simple) fibrosis with HCC Less than Accumulation Excess fat acts Scar tissue Repeated and/or Extensive scar Patients with 5% fat1 of fat in the as a toxin and begins to form continuous liver tissue and NASH have a liver. Steatosis damages healthy in the liver as damage/repair regenerated 2%–20% 5-year is defined as liver cells. it attempts results in nodules replace cumulative intrahepatic fat This results in to repair and widespread and most all healthy incidence of of at least 5% steatohepatitis replace damaged permanent tissue and hepatocellular of liver weight3 (NASH)4, 5 cells7, 9 non-functioning inhibits liver carcinoma scar tissue7, 9 function9 (HCC)10 Figure 4: Categories of nonalcoholic fatty liver disease progression from normal liver through to cirrhosis with the potential complication of liver cancer.10 While not all individuals will progress to a cirrhotic or cancerous state, early knowledge of the presence of disease can allow intervention or treatment that can work toward lowering that risk. NAFLD and obesity In addition to metabolic disorders and certain in 1975 to just over 18% in 2016.12 In 2016 WHO medications being causative factors, NAFLD is usually statistics put over 340 million children and adolescents seen in people who are overweight or obese.10 In in this age group as either being overweight or obese.12 a study of more than 8 million people, obesity was While the concentration of NAFLD per country does vary, present in 51% of patients with NAFLD and 82% of the worldwide incidence is estimated to be 25%.11 Since patients with NASH.11 This is very worrisome, as the obesity affects all races, the prevalence of NAFLD will most current statistics from 2016 by the World Health increase at approximately the same rate as obesity.11 Organization (WHO) state that worldwide, more than Even now, nonalcoholic fatty liver disease is becoming 1.9 billion adults 18 years and older are considered so prevalent worldwide that NASH is quickly becoming overweight, and of that number, 650 million are one of the leading indications for liver transplant.3 categorized as obese.12 Even more troubling is being overweight or obese has expanded downward in age to include children. The prevalence of obesity and being overweight among children and adolescents aged 5–19 years has risen dramatically from just 4% siemens-healthineers.com/ultrasound 7 White paper · Ultrasound Derived Fat Fraction (UDFF) Current Practices for Diagnosis Why is it essential to diagnose fatty liver at an early Proton Density Fat Fraction (PDFF) stage? Early detection of hepatic steatosis improves the chances of managing or reversing the condition before Magnetic resonance spectroscopy (MRS) is considered irreversible changes can occur.2 At present, there are the most sensitive, noninvasive modality for the existing medical techniques (imaging and non-imaging) detection and quantification of hepatic steatosis.2 that can diagnose hepatic fat content. These techniques Magnetic resonance spectroscopy exploits the difference vary in degrees of effectiveness, cost, invasiveness, in resonance frequencies between water and fat proton availability [of equipment] and/or patient suitability. signals to quantitatively measure the proton density fat fraction (PDFF).2 PDFF is defined as the ratio of mobile triglyceride protons to the sum of the mobile triglyceride Liver biopsy and water protons.13 The resultant index is a marker of fat. Several studies have reported that the fat fraction Currently, liver biopsy is the reference standard for measured by MRS closely correlates with the histologic diagnosing and grading hepatic steatosis. Liver biopsy assessment of liver fat content. Despite the high accuracy is, however, inappropriate for screening or frequent of MRS for quantifying the fat fraction, its use is limited monitoring as it is invasive, prone to sampling errors, as it is time-consuming to perform and analyze, and observer variability, and the risk of complications.2 samples only a small portion of the liver.2 There is a need to develop less invasive objective Rapid chemical shift-based magnetic resonance imaging quantitative biomarkers for the diagnosis of hepatic (MRI) techniques have been developed that can steatosis. Currently this need is largely unmet, which accurately quantify liver fat across the entire liver. causes people to go undiagnosed. Additionally, the lack These techniques involve water-fat separation, as MRI is of noninvasive testing techniques represents a major sensitive to the signal from protons in mobile, unbound barrier for drug development in NASH, as treatment molecules, such as water and triglycerides.3 MRI response assessment continues to require liver biopsy.3 accomplishes this phenomenon by acquiring images at Most recent noninvasive avenues involve magnetic 2 or more echo times after signal excitation.2 MRI-PDFF resonance spectroscopy (MRS) and chemical shift-based then exploits the difference in resonance frequencies magnetic resonance imaging (MRI).2 of protons in water and fat to provide an estimate of 8 siemens-healthineers.com/ultrasound Ultrasound Derived Fat Fraction (UDFF) · White paper tissue fat fraction. This index is calculated by separating measurement may be decreased.16 Contra-indications the signals from water and fat then calculating the for CAP usage include patients who have an implanted percentage using the individual fat value over the pacemaker, which is thought to make up about 5% of combined value of fat and water. The PDFF index is the patient population, and patients who are pregnant.17 expressed as a percentage (%) and ranges from 0 to 100%. Fat Conventional ultrasound x 100% Fat + Water Conventional ultrasound is the most common imaging modality for assessing hepatic steatosis. In conventional MRI-PDFF estimation is shown to be accurate and ultrasound, assessment is made based on qualitative reproducible with good correlation to the histological features of the B-mode images of the liver.2 These steatosis grade assigned to specimens obtained from include: liver biopsies.2 The MRI-PDFF technique does suffer from some limitations which include high cost, low • Liver parenchymal echogenicity appearance accessibility, long scan times, sedation of young children, • Signal loss at depth (penetration) and the exclusion of patients with metal implants. • Liver texture • Ability to visualize vessels and the diaphragm clearly • Presence/absence of focal fatty sparing Controlled Attenuation Parameter (CAP) • Increased hepatorenal echogenicity The sensitivity and specificity of conventional ultrasound Controlled Attenuation Parameter (CAP) is another for the detection of moderate-to-severe fatty liver is noninvasive method used to evaluate hepatic steatosis. high, however the sensitivity decreases markedly in The degree of fat present in the liver is estimated using incidents of mild steatosis where less than 30% of a non-imaging ultrasound-based device. The piston-like hepatocytes are affected.2 Conventional ultrasound transducer is placed between the ribs on the right side assessment techniques also suffer from operator and of the patient where it can emit an ultrasound wave machine dependency, which leads to variability in the that will travel through the liver.14 The CAP value is an detection and/or severity of hepatic steatosis.2 estimate of the attenuation of the emitted ultrasound wave as it propagates through the liver. This value is calculated from data acquired by either the traditional Hepatorenal index CAP method consisting of several manually-triggered sequential measurements (typically 10), or the The hepatorenal index was developed to remove subsequent continuous CAP method, where the subjectivity associated with qualitative interpretations transducer remains in contact with the skin surface of B-mode images.2 The hepatorenal index quantifies for several seconds while acquiring “continuous” liver echogenicity relative to the kidney and has a good [attenuation] data.15 CAP is reported in decibels per correlation with the degree of steatosis. The hepatorenal meter (dB/m) and has a range of 100–400 dB/m. Since index measurement does have limitations, most notably, fat affects ultrasound propagation through absorption the comparison cannot be performed on patients who and scattering leading to signal attenuation, a higher have renal disease that affects the cortical echogenicity fat content within the liver will translate to a higher of the kidney. Another limitation is finding proper CAP value. While CAP can be performed rapidly and imaging windows to place 2 regions-of-interest (ROIs) painlessly, it has several challenges that can prevent at the same depth within the kidney cortex and the liver use in certain patient populations and/or lend itself to parenchyma.2 the inability of the operator to avoid certain artifacts. Unlike conventional ultrasound, where the liver and surrounding structures are visualized on the imaging screen, CAP is a non-imaging or “blind” test. The lack of visualization of the liver can result in the inability of the user to avoid fluid-filled vascular structures or unknown ascites in a patient, both of which can affect results. Additionally, in patients with a body mass index (BMI) higher than 30 (obese), the accuracy of the CAP siemens-healthineers.com/ultrasound 9 White paper · Ultrasound Derived Fat Fraction (UDFF) Ultrasound Derived Fat Fraction (UDFF) What is UDFF? Ultrasound Derived Fat Fraction (UDFF) is a unique new UDFF delivers a similar clinical utility to Magnetic technology available on the ACUSON Sequoia ultrasound Resonance Imaging Proton Density Fat Fraction system to noninvasively quantify fat in the liver. The (MRI-PDFF) for determining hepatic steatosis. Both Ultrasound Derived Fat Fraction provides an index of methods classify hepatic steatosis as an index value hepatic fat content in a region-of-interest (ROI) of greater than 5%. positioned within the liver by the user. With a total exam time of less than 1 minute*, the The UDFF index is estimated from both the Attenuation Ultrasound Derived Fat Fraction is a measurement tool Coefficient (AC) and the Backscatter Coefficient (BSC). to aid physicians in managing adult patients as part of The resulting UDFF index is displayed in percent (%) and an overall assessment of hepatic steatosis. has a range of 0–100%. The UDFF index exhibits a linear relationship with fat content such that the higher the UDFF index value, the higher the fat content level is within the liver. * Based on 5 UDFF acquisitions when used as a stand-alone feature. 10 siemens-healthineers.com/ultrasound Ultrasound Derived Fat Fraction (UDFF) · White paper a. No attenuation b. Moderate attenuation c. High attenuation DAXACUSON DAXACUSON DAXACUSON MAMAC Figure 5: Tissue attenuation can be determined by estimating the frequency content of the sound at different depths then comparing them to values taken from a known reference. This method allows us to isolate the attenuation of the tissue and estimate its attenuation coefficient. In figure 5, the slope of the orange line is related to the attenuation within tissue; the greater slopes indicate greater attenuation coefficient values. No attenuation or almost no attenuation would be seen when imaging in water (a) whereas moderate to high attenuation (b, c) would be seen in soft tissues (liver, kidney, fat etc.). Attenuation Coefficient (AC) As sound propagates through the body it is absorbed visualize deeper structures. The Attenuation Coefficient by tissue reducing the amplitude and intensity of the describes the rate of decay of the ultrasound energy ultrasound wave (Figure 5). The rate of absorption is as it propagates through a tissue and is a quantitative dependent on frequency, tissue type and depth. Higher measure for tissue obscuration as visually assessed from frequency sound waves are absorbed by the body more a B-mode image. quickly than lower frequencies, which is often a factor in Attenuation alone is not sufficient for estimating fat transducer selection. Attenuation rate is also influenced by tissue type, as not all tissues attenuate sound waves content in the liver. Microscopic tissue properties, such at the same rate. Sound propagating through fatty tissue as the size of a fat cell, affect the backscattered echo will tend to be more readily absorbed than through signals. The addition of the backscatter coefficient non-fatty tissue. We experience the phenomenon of provides another piece of information which allows sound absorption constantly during an ultrasound exam us to estimate the percentage of fat in the liver with and try to accommodate for it by changing to a lower improved accuracy. frequency transducer or exam frequency setting to help siemens-healthineers.com/ultrasound 11 White paper · Ultrasound Derived Fat Fraction (UDFF) a. b. c. d. DAXACUSON DAXACUSON DAXACUSON DAXACUSON WW Ww Figure 6: Cell size has a direct influence on the amount of backscatter that occurs. The larger the cell, the greater the degree of sound reflections and scatter that occurs. Figure (a) depicts a small fat particle interacting with the propagating sound wave (orange arrow). When the sound wave interacts with the small fat cell only a small amount of reflection and/or scattering occurs (b, green arrow). Figures (c) and (d) depict the same sound wave interaction but with a larger fat cell. The larger cell produces a greater amount of reflection and/or scattering due to the larger surface area with which the sound wave interacts. Backscatter Coefficient (BSC) The Backscatter Coefficient (BSC) describes the scattering The larger “obstructive” fat cells interfere with the properties of the underlying tissue and can be measured sound wave more intensely. This results in a higher from the strength of the scattered ultrasound signal amount of reflection and scattering of the sound back (brightness) at a particular frequency. The BSC contains to the transducer (Figure 6c–d). In 2D scanning we information relating to the microstructure of the see the intensity of the backscatter depicted as a underlying tissue, in particular, fat globules. While it bright “fatty” liver image. We use the backscatter is normal to have a small amount of fat in the liver, coefficient qualitatively when we visually compare continued deposition causes the fat cells to increase in the liver brightness to that of the kidney. This visual size. As the fat cells enlarge, they begin to reflect and brightness assessment based on perceived BSC has scatter sound differently than normal sized liver and fat morphed into the semi-quantitative hepatorenal index cells. Smaller fat cells have little interference on the (HRI) measurement. The HRI indirectly compares the sound wave when compared to healthy liver tissue. This BSC of the liver to the BSC of the kidney with a larger results in a small amount of backscatter (Figure 6a–b). value indicative of higher liver fat content. 12 siemens-healthineers.com/ultrasound Ultrasound Derived Fat Fraction (UDFF) · White paper 45 40 35 30 25 20 15 MRI-PDFF (%) 10 5 0 -5 0 5 10 15 20 25 30 35 UDFF (%) Figure 7: The backscatter coefficient is an acoustic tissue parameter which provides a direct relationship to the microstructure of liver; however, the relationship between BSC and fat content is nonlinear. UDFF is a linearization of the BSC to provide a 1:1 relationship between the UDFF index and the fat content. Calculating UDFF The UDFF index value is calculated from the AC and the using a unique proprietary mathematical algorithm. BSC values. These values are determined by comparing This mathematical procedure (P) converts BSC into the the frequency content of the backscattered echo signals UDFF index in units of percent (BSC at 3 MHz is linearized at different depths within the tissue to the frequency to provide the UDFF index). content of a tissue mimicking reference phantom. The AC and BSC values of the reference phantom are P pre-characterized. This comparison allows us to isolate BSC (3 MHz) → UDFF the attenuation of the tissue and estimate its AC. Likewise the ratio of the two frequency spectra, along Unlike the AC and BSC values, the UDFF index exhibits with estimated AC of that phantom, can be used to a linear relationship with the fat content – as the UDFF estimate the BSC of the tissue sample. Following BSC index value increases, so does the fat content level. estimation, the value for the UDFF index is finally The UDFF index demonstrates similar clinical utility to calculated from the BSC of the tissue sample at 3 MHz MRI-PDFF (Figure 7).2 siemens-healthineers.com/ultrasound 13 White paper · Ultrasound Derived Fat Fraction (UDFF) Comparing UDFF to other fat Validating UDFF quantification technologies The UDFF index is calculated from the AC and the At present, the most widely accepted noninvasive BSC of the liver using a reference phantom method. imaging modality to characterize fat content in the This method is repeatable and reproducible between liver is MRI-PDFF. MRI-PDFF is a quantitative imaging transducers in adults with known or suspected NAFLD.18 biomarker that enables accurate, repeatable, and Using histologic steatosis grades as reference, the reproducible quantitative assessment of liver fat over diagnostic accuracy of the UDFF index in detecting the entire liver.3 MRI-PDFF provides a specific fat content the presence of steatosis (> 5% hepatocytes) was 0.94 number, in percent, between 1–100%. The cost, exam (0.85–0.98), which is comparable to the diagnostic time and ease of availability makes routine usage of accuracy of MRI-PDFF: 0.94 (0.81–0.98).2 The sensitivity MRI-PDFF challenging, thus other more cost-effective and specificity of UDFF were 0.84 (0.76–0.92) and 1.0 and widely available fat quantifying tools have been (1.0–1.0) respectively compared to 0.80 (0.71–0.87) and developed – but how do they compare? 1.0 (1.0–1.0) for MRI-PDFF. Using MRI-PDFF as reference, Controlled attenuation parameter, or CAP, estimates the diagnostic accuracy of the UDFF index in detecting ultrasound energy decay and then analogues it to the the presence of steatosis (MRI-PDFF > 5%) was 0.97 attenuation coefficient estimation. The obtained CAP (0.93–0.99) with sensitivity of 0.94 (0.87–0.97) and value (displayed in decibels per meter [dB/m]) along specificity of 1.0 (1.0–1.0).2 The mean bias between with the patient’s proposed etiology, is then charted to MRI-PDFF and the UDFF index was close to zero determine a steatosis stage corresponding to that of indicating good agreement between UDFF and histology. For example, a patient with a CAP value of MRI-PDFF; the limits of agreement were ± 8.5%. The 305 dB/m with a NAFLD/NASH etiology is classed as Pearson correlation coefficient was 0.87 indicating being an S1 steatosis grade with a corresponding fat good correlation between UDFF and MRI-PDFF.2 content range of 5–33%.19 Ultrasound imaging techniques have emerged that are based solely on measuring the level of attenuation to determine the liver fat content. These techniques, unlike MRI-PDFF, do not determine a fat percentage but rather the resulting attenuation coefficient that is graded against fat content – the higher the attenuation coefficient, the higher the degree of fat contained within the liver. These techniques provide a result that is like CAP in that the value of the attenuation coefficient is then assigned a grade (S0, S1, etc.) with an associated fat range. Like CAP, these results are not in the same unit (percent) as MRI-PDFF. 14 siemens-healthineers.com/ultrasound Ultrasound Derived Fat Fraction (UDFF) · White paper Summary Receiver Operating Characteristic (ROC) Curve 1.0 MRI-PDFF UDFF CAP 0.8 0.6 0.4 True Positive Rate (Sensitivity) 0.2 0.0 0.0 0.2 0.4 0.6 0.8 1.0 False Positive Rate (Specificity) Figure 8: A meta-analysis comparing MRI-PDFF, CAP and UDFF demonstrates that the Ultrasound Derived Fat Fraction has a similar diagnostic performance to that of MRI-PDFF and CAP in detecting the presence of steatosis.20 UDFF is unique in that it measures both attenuation of MRI-PDFF and CAP. The analysis is summarized in and backscatter and then uses those results to calculate a Receiver Operating Characteristic (ROC) curve in a UDFF index. The UDFF index is displayed in percent Figure 8. The performance of the given technologies and demonstrates a similar clinical utility to that of is visualized with sensitivity on the Y-axis and specificity MRI-PDFF – the most widely accepted and repeatable on the X-axis. The accuracy of each technology is fat quantification method. Since UDFF uses the same defined by the area under the curve (AUC). unit and > 5% classification criteria as MRI-PDFF, there is no need to convert the result or consult a chart to For this meta-analysis, the diagnostic accuracy was the determine the liver fat content. Sufficient agreement highest for MRI-PDFF (AUC = 0.91) as denoted by the between the modalities enables rapid adoption of a black dot in Figure 8. The green dot, representing the less expensive and time-consuming modality enabling controlled attenuation parameter (CAP), had an AUC better use of health care resources. of 0.81. The Ultrasound Derived Fat Fraction (UDFF) identified by the orange dot, demonstrated an AUC of For validation, a meta-analysis was done to compare 0.88. The results of this meta-analysis supports the claim the diagnostic performance of UDFF in detecting that UDFF demonstrates a similar clinical utility to that the presence of steatosis (> 5% fat content) with that of MRI-PDFF.20 siemens-healthineers.com/ultrasound 15 White paper · Ultrasound Derived Fat Fraction (UDFF) Scanning Protocol and Clinical Examples To perform a UDFF measurement, the patient should fast are ready to acquire your measurement. When you wish for at least 4 hours prior to the exam. Position the patient to activate the measurement, have the patient suspend/ in a supine or slight (30º) left lateral decubitus position pause their breathing/respiration. The patient can with the right arm raised above their head. This is resume normal respiration once the audible tone is optimal positioning to improve intercostal access. Place heard indicating the acquisition is complete. A single the transducer perpendicular (90º) to the skin surface UDFF measurement is made within the ROI and will be using ample gel. Transducers that are not perpendicular displayed as a percent (%) within the measurement will have an inadequate transducer angle and can result display area (MDA) (Figure 9). Siemens Healthineers in artificially low measurement values. Select an artifact- recommends 5 UDFF measurement samples be acquired free area within the right lobe of the liver to place the for a complete exam study. Once all measurements are region-of-interest (ROI). An artifact-free area is defined obtained, the patient report will display each individual as an area free from vessels, large hepatic ducts, bright measurement with the associated depth as well as reflectors, and rib shadows. Ensure the liver capsule the Mean, Median, Standard Deviation, Interquartile marker is aligned flat/parallel with the echogenic range (IQR), and IQR/Median ratio for all acquired interface of the liver capsule when placing the ROI. measurements (Figure 10). A normal UDFF index liver Proper placement of the marker ensures that the sample fat level is less than or equal to 5% (Figure 11) while is taken at least 1.5 to 2 cm below the liver capsule an abnormal UDFF index value is above that threshold (Figure 9). Have the patient breathe normally until you (Figure 12, Figure 13). 16 siemens-healthineers.com/ultrasound Ultrasound Derived Fat Fraction (UDFF) · White paper DAX Liver Site 5 Abdomen Liver Site 1 UDFF=10 % TIB:0.85 UDFF Depth Depth=5.5 cm TIC:2.44 TIS:0.85 % cm MI:1.38 20fps 5.7 95% 11 5.5 2D 10 5.5 H Low 5.5 -4dB/DR60 5.5 LAWN - c=1540 Mean 8.8 PSWE Std Dev 1.6 Median 8.0 IQR 3.0 IQR/Median 0.4 Overall Statistics Mean 8.8 % Std Dev 1.6 % Median 8.0 % IQR 3.0 % IQR/Median 0.4 16cm Cooling 6 Figure 9: To ensure proper ROI positioning and placement, align the Figure 10: The total number of acquisitions and associated data “+” marker of the sample line parallel with the liver capsule. Aligning will be displayed in the patient report. Siemens Healthineers the sample marker places the ROI at the recommended 1.5–2 cm recommends 5 separate acquisitions for a complete UDFF exam. depth below the liver capsule as well as ensures the sample is placed at the proper perpendicular position optimal for acquisition. DAX DAX Liver Site 1 Abdomen Liver Site 1 Abdomen UDFF=4 % TIB:0.17 TIC:0.52 UDFF=11 % TIB:0.85 Depth=5.0 cm TIC:2.44 TIS:0.17 Depth=5.5 cm TIS:0.85 MI:1.37 MI:1.38 20fps 20fps 95% 2D 2D H Mid H Low 0dB/DR60 0dB/DR60 c=1540 c=1540 PSWE PSWE 13cm 16cm Cooling 9 Figure 11: A normal liver contains a small amount of fat – less than Figure 12: Abnormal UDFF index measurement is above the 5% or equal to 5%. A normal UDFF index value uses the same threshold. threshold. DAX Liver Site 1 Abdomen UDFF=25 % TIB:0.19 Depth=5.9 cm TIC:0.55 TIS:0.19 MI:1.38 21fps 95% 2D H Low 1dB/DR60 c=1540 LD 3 UA 2 MapC/T5 P3 PSWE 14cm Figure 13: Since nonalcoholic fatty liver disease is usually seen in people who are overweight or obese,10 the deep abdominal transducer (DAX) is a useful tool to help penetrate the liver. An abnormal UDFF index measurement of 25% is noted in this high BMI patient.10 siemens-healthineers.com/ultrasound 17 White paper · Ultrasound Derived Fat Fraction (UDFF) Conclusion Nonalcoholic fatty liver disease is currently the most Ultrasound Derived Fat Fraction (UDFF) is an innovative common cause of chronic liver disease worldwide.3 Fatty advanced application available for use on the ACUSON liver, or hepatic steatosis, occurs when fat molecules are Sequoia ultrasound system that can quantify the amount not metabolized efficiently enough by the body and end of fat contained within a patient’s liver. UDFF can up stored in the liver. While a normal liver contains a quantify fat content in just seconds* during a routine small amount of fat, the liver is considered “fatty” if the abdominal ultrasound. UDFF delivers a similar clinical amount of fat within the hepatocytes exceeds 5%.1 utility to MRI Proton Density Fat Fraction (MRI-PDFF) Early detection of hepatic steatosis improves the chances to aid clinicians in determining hepatic steatosis. of managing or reversing the condition before irreversible MRI-PDFF and UDFF methods classify hepatic steatosis changes can occur.2 At present, the existing medical as an index value greater than 5%. With the use of this techniques that can diagnose hepatic fat content vary in simple tool, physicians now have a new, noninvasive way degrees of effectiveness, cost, invasiveness, availability to help manage adult patients** with hepatic steatosis. of equipment, and/or patient suitability. There is a need to develop less invasive and objective quantitative biomarkers for the diagnosis of hepatic steatosis that is cost-effective and widely available. * Based on 5 UDFF acquisitions when used as a stand-alone feature. ** When used as part of an overall assessment of hepatic steatosis. 18 siemens-healthineers.com/ultrasound Ultrasound Derived Fat Fraction (UDFF) · White paper Citations 1 Nassir F, Rector RS, Hammoud GM, Ibdah JA. Pathogenesis and 12 https://www.who.int/news-room/fact-sheets/detail/obesity-and- Prevention of Hepatic Steatosis. Gastroenterology & Hepatology. overweight Vol 11, Issue 3; 167 – 175. Mar 2015. 13 Kim M, Kang BK, Jun DW. Comparison of conventional 2 Labyed & Milkowski 2021; JUM 39(12) p2427-2428, doi: sonographic signs and magnetic resonance imaging proton 10.1002/jum.15364 density fat fraction for assessment of hepatic steatosis. Sci 3 Caussy Cyrielle, Reeder Scott B, Sirlin Claude B, Loomba Rohit. Rep 8, 7759 (2018). Non-invasive, quantitative assessment of liver fat by MRI-PDFF as an endpoint in NASH trials. Hepatology. 2018 Aug; 68(2): 14 Mikolasevic, Ivana et al. Transient elastography (FibroScan(®)) 763-772. Doi:10.1002/hep. 29797 with controlled attenuation parameter in the assessment 4 Idilma IS, Aniktar H, Idilman R, et al. Hepatic steatosis: of liver steatosis and fibrosis in patients with nonalcoholic quantification by proton density fat fraction with MR imaging fatty liver disease - Where do we stand?. World journal of versus liver biopsy. Radiology 2013:267:767-775 gastroenterology vol. 22,32 (2016): 7236-51. doi:10.3748/ wjg.v22.i32.7236 15 Audière S, Labourdette A, Miette V, Fournier C, Ternifi R, et al.. 5 Wilkins T, Tadkod A, Hepburn I, Schade RR. Nonalcoholic Fatty Liver Disease: Diagnosis and Management. American Family Improved ultrasound attenuation measurement method for the Physician. July 1, 2013. Vol 88, Num 1: 35 – 42. non-invasive evaluation of hepatic steatosis using FibroScan ® . Ultrasound in Medicine & Biology, Elsevier, In press. 6 Petaja EM and Yki-Jarvinen. Definitions of Normal Liver Fat and hal-03290919 the Association of Insulin Sensitivity with Acquired and Genetic NAFLD – A Systematic Review. In J Mol Sci. 2016, 17, 633. 16 https://www.mskcc.org/cancer-care/patient-education/ understanding-your-fibroscan-results 7 https://my.clevelandclinic.org/health/diseases/15831-fatty-liver- disease 17 Shen, Feng et al. Controlled attenuation parameter for non-invasive assessment of hepatic steatosis in Chinese 8 https://www.mayoclinic.org/diseases-conditions/ patients. World journal of gastroenterology vol. 20,16 (2014): nonalcoholic-fatty-liver-disease/symptoms-causes/syc-20354567 4702-11. doi:10.3748/wjg.v20.i16.4702 9 Li Q, Dhyani M, Grajo JR, Sirlin C, Samir AE. Current status of 18 Nam, K, Zagzebski, JA, and Hall, TJ. Simultaneous Backscatter imaging in nonalcoholic fatty liver disease. World J Hepatol. and Attenuation Estimation Using a Least Squares Method 2018;10(8):530-542. doi:10.4254/wjh.v10.i8.530 with Constraints. Ultrasound Med Biol. 2011 December; 10 https://www.myliverexam.com/en/understand-the-liver/state/ 37(12): 2096-2104 steatosis/ 19 Echosens interpretation guide via MyFibroScan free app 11 Younossi Zobair M. Non-alcoholic fatty liver disease – A global (available for download on Google Play or Apple App Store) public health perspective. Journal of Hepatology. 2019 vol 20 Data on file with Siemens Healthineers 70|531-544 siemens-healthineers.com/ultrasound 19 At Siemens Healthineers, our mission is to enable Standalone clinical images may have been cropped healthcare providers to increase value by empowering to better visualize pathology. The products/features them on their journey towards expanding precision mentioned in this document may not be commercially medicine, transforming care delivery, and improving available in all countries. Due to regulatory reasons, patient experience, all enabled by digitalizing healthcare. their future availability cannot be guaranteed. An estimated five million patients worldwide everyday Please contact your local Siemens Healthineers benefit from our innovative technologies and services organization for further details. in the areas of diagnostic and therapeutic imaging, laboratory diagnostics and molecular medicine as well ACUSON Sequoia is a trademark of Siemens Medical as digital health and enterprise services. Solutions USA, Inc. We’re a leading medical technology company with over 120 years of experience and 18,500 patents globally. With over 50,000 employees in more than 70 countries, we’ll continue to innovate and shape the future of healthcare. Siemens Healthineers Headquarters Manufacturer Siemens Healthcare GmbH Siemens Medical Solutions USA, Inc. Henkestr. 127 Ultrasound 91052 Erlangen, Germany 22010 S.E. 51st Street Phone: +49 9131 84-0 Issaquah, WA 98029, USA siemens-healthineers.com Phone: 1-888-826-9702 siemens-healthineers.com/ultrasound Published by Siemens Medical Solutions USA, Inc. · 10916 1021 online © Siemens Medical Solutions USA, Inc., 2021