Noninvasive assessment of liver steatosis with ultrasound techniques

Introduction

Worldwide, obesity has nearly tripled since 1975. The World Health Organization (WHO) reports that, as of 2016, more than 1.9 billion adults 18 years or older were overweight, and, of these, over 650 million were obese. The WHO report underscores that most of the world’s population lives in countries where overweight and obesity kills more people than underweight. As for children, the report estimated that over 340 million children and adolescents aged 5–19 years old were overweight or obese in 2016. A modeling study suggests that by 2030, the prevalence of nonalcoholic steatohepatitis (NASH) will increase 63% from the estimation made in 2015, and liver mortality and advanced liver disease are expected to more than double. These increases in the rates of obesity have prompted the WHO to identify obesity as one of the nine global noncommunicable diseases that must be addressed.

Obesity increases the risk of several diseases including nonalcoholic fatty liver disease (NAFLD), which is currently the most prevalent chronic liver disease worldwide. In fact, the prevalence of NAFLD is proportional to the increase in body mass index.

In a large U.S. cohort of asymptomatic middle-aged adults, the prevalence of NAFLD was 38% and the prevalence of NASH was 14%. Factors associated with the presence of NASH were race, obesity, and diabetes.

The rate of individuals affected by type 2 diabetes mellitus, which is another important risk factor for NAFLD and NASH, is also growing worldwide. Of note, it seems that type 2 diabetes mellitus seems to accelerate the course of NAFLD and is a predictor of advanced fibrosis and mortality. Moreover, liver steatosis can negatively affect the disease progression and treatment response in patients with viral hepatitis C and the prognosis of hepatic transplantation recipients.

NAFLD seems the most common cause of abnormal serum aminotransferase levels as well as chronic liver disease in the Western world. It is an umbrella term that includes a disease spectrum ranging from benign steatosis to NASH. The latter may progress to liver cirrhosis with its complications, namely portal hypertension and hepatocellular carcinoma. The prevalence of NAFLD in the general population is about 25% and it increases to over 90% in morbidly obese individuals. The progression to fibrosis is about 40%, and the mean annual rate of progression in NASH is 0.09%. The reason why some patients with NAFLD, even those with a low amount of fat in the liver, will develop NASH is still not clearly understood. The degree of liver steatosis is linked to metabolic syndrome and the cardiovascular risk. On the other hand, it seems that significant steatosis is associated with progression of fibrosis in patients with NAFLD. It also must be highlighted that a recent nationwide study in Sweden has shown in an adult cohort that the hazard ratio for overall mortality was significantly higher in all patients with NAFLD, including those with simple steatosis, than in controls. The results of this study confirm previous findings in small cohorts of patients with NAFLD with paired liver biopsy, ^, suggesting that simple steatosis may clearly progress, with around one quarter of patients developing bridging fibrosis over a relatively short time period. Of note, baseline steatosis grade was higher in those with progressive fibrosis. Alarmingly, similar findings were observed in children and young adults with biopsy-confirmed NAFLD: they had significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality compared with matched general population controls. Simple steatosis was associated with a 5.26-fold higher adjusted rate of mortality compared with controls.

Therefore an accurate estimate of the quantity of the fat in the liver is of great importance in the diagnostic work-up of patients with liver steatosis.

A panel of experts has recently proposed to adopt a new term based on a holistic approach to the disease, metabolic dysfunction–associated fatty liver disease (MAFLD). The diagnosis of MAFLD is based on the evidence of liver steatosis together with three positive criteria: overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation.

In this chapter, we mostly use the term NAFLD because of the criteria that were followed to enroll patients in the cited studies.

Reference standard for liver fat quantification

For decades, liver biopsy has been considered the reference standard for detecting and grading liver steatosis. In the histologic Kleiner classification, the amount of fat in the liver is graded as S0, steatosis in less than 5% of hepatocytes; S1, 5%–33%; S2, 34%–66%; and S3, more than 66%.

Liver biopsy is an invasive procedure with some risks of complications that can be severe in up to 1% of cases. ^, On the other hand, the biopsy specimen is obtained from a very small part of liver, and fatty infiltration could be heterogenous. Moreover, a substantial intraobserver and interobserver variability between readings has been reported. ^, Considering the obesity epidemic, biopsy is not a practical approach for screening in patients with MAFLD who may have simple steatosis in most cases. Liver steatosis is a dynamic process that may change in short periods of time (weeks), requiring a noninvasive technique that can be repeated at multiple times to accurately assess progression or regression of disease.

Magnetic resonance imaging–derived proton density fat fraction (MRI-PDFF) is a quantitative noninvasive biomarker that objectively estimates the liver fat content and has been accepted as an alternative to the histological assessment of liver steatosis in patients with MAFLD. MRI-PDFF is not influenced by confounding factors, including body weight, and is operator-independent. Currently, it is an accepted noninvasive tool to diagnose and quantify liver steatosis and is used in clinical trials as an accurate reference standard method as an alternative to liver biopsy. ^, Also, when assessing the performance of new noninvasive tools for the detection and grading of liver steatosis, liver biopsy is not the best reference to compare the results with, given the very small size of the biopsy specimen and the dynamic nature of liver fat content.

The ultrasound (US) attenuation working group of the American Institute of Ultrasound in Medicine (AIUM) and the Radiological Society of North America (RSNA) Quantitative Imaging Biomarkers Alliance (QIBA) Pulse Echo Quantitative Ultrasound (PEQUS) initiative, which was formed to help develop and standardize acquisition protocols and to better understand confounding factors of US-based fat quantification, has recently advised that MRI-PDFF should be used in studies as the reference standard.

Noninvasive assessment: Ultrasound

Semiquantitave assessment

Hamaguchi score

The Hamaguchi score combines four US findings: hepatorenal echo contrast, bright liver, deep attenuation, and vessel blurring, and a number is assigned to each of them.

Hepatorenal echo contrast is based on the ultrasonographic contrast between the hepatic and right renal parenchyma evaluated in an intercostal scan in the mid-axillary line; bright liver is based on abnormally intense high level echoes arising from the liver parenchyma and is graded as none, mild, or severe in accordance with intensity brightness; deep attenuation is based on the US attenuation in the deep portion of the liver and impaired visualization of the diaphragm; vessel blurring is based on impaired visualization of the borders of the intrahepatic vessels and narrowing of their lumen ( Fig. 11.1 ).

Bright liver and hepatorenal echo contrast are evaluated together, and the score ranges from 0 to 3. If they are both negative, the final score is 0. Deep attenuation goes from 0 to 2, and vessel blurring can be positive (score 1) or negative (score 0).

In a small series of patients undergoing liver biopsy, Hamaguchi et al. found that a score ≥2 had 91.7% sensitivity and 100% specificity for diagnosing NAFLD with an area under the receiver operating characteristic curve (AUROC) of 0.98. A score ≥1 had high specificity (95.1%) to detect visceral obesity. However, this score has not been validated in large series of patients.

Ultrasonographic fatty liver indicator score

The ultrasonographic fatty liver indicator (US-FLI) score is based on the following features: intensity of liver/kidney contrast, posterior attenuation of the US beam, vessel blurring, difficult visualization of the gallbladder wall, difficult visualization of the diaphragm, and areas of focal sparing. Focal fat sparing is considered to be present when a focal geographic hypoechoic area is observed next to the gallbladder wall, portal vein, or the falciform ligament ( Fig. 11.2 ).

“Conditio sine qua non” is the presence of the contrast between the liver and the kidney, which is scored 2 if mild/moderate and 3 if severe. The presence of each other finding is scored 1.

The score ranges from 2 to 8 and NAFLD is diagnosed by a score at least >2.

In a small series of nonconsecutive patients, using liver histology as the reference, it has been reported that the US-FLI score was an independent predictor of NASH and a US-FLI <4 had a high negative predictive value (94%) in ruling out the diagnosis of severe NASH, but its specificity was low (45.7%). The AUROCs were 0.76 for the diagnosis of NASH and 0.80 for the diagnosis of severe NASH. As for the Hamaguchi score, the US-FLI score still lacks validation.

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