IMAGING-BASED MODALITIES IN NAFLD Dr. Assem El-Shendidi Hepatology Unit Alexandria Faculty of Medicine

Does My Patient Have NAFLD ? Is My Patient At Risk Of Progressive Disease ? Does My Patient Have Any Fibrosis or Advanced Fibrosis ? When a clinician sees a patient with fatty liver in a clinical setting, three broad clinical questions emerge:

LIVER BIOPSY Standard for assessment of liver disease severity (Detect hepatic steatosis- Diagnose NASH- Stage fibrosis). Invasiveness – Variability (sample or observer) – Morbidity (pain or bleed or infection) and, albeit rarely, Death. Impractical for screening the millions of asymptomatic at-risk individuals or for monitoring the changes in fibrosis stage over time. Liver Biopsy can give the answer for all these questions However, limitations include Hence, it is not such ideal

IDEAL BIOMARKER Noninvasive - Accurate – Objective – Quantitative – Reproducible – Help Risk Stratification of patients who may need intervention. Serum-based markers: Limited value Imaging-based markers: Texture – Diffusion – Amount of the fat – Bond Number in the fat – Elasticity "Stiffness" Imaging can assess different properties of the tissue

ASSESSMENT OF LIVER FAT CONTENT We will focus initially on how imaging modalities can be used to diagnose NAFLD

CUS Point-of-care imaging modality for liver fat assessment. Widely available, safe, tolerated, inexpensive. Radiographic features interpreted qualitatively and subjectively (echogenicity of liver relative to right kidney) (obscuration of some liver structures). However,

CUS Patient factors (Obesity – coexistent renal disease). Acquisition factors (Scanner – Transducer – Settings – Operator). Not sensitive but specific for detection of dense fatty infiltration. Neither sensitive nor specific for liver fat quantification. Accuracy and reproducibility is limited particularly in obese individuals And these radiographic features are affected by many →.

CAP US-based tool for assessment of liver fat content. A threshold CAP reading of 288 db/sec shows high accuracy for the detection of hepatic steatosis. CAP readings are likely to be highly reliable if IQR is less than 30 db/sec variability. Recent studies have shown that QUS may be superior to CUS to detect and quantify hepatic steatosis IQR: Measure of statistical dispersion. Measure of variability based on division of a rank-ordered data set into four equal parts (quartiles). Equal to the difference between 75th and 25th percentiles. Equal to the difference between the upper and the lower quartiles.

CAP Quantitative estimate of liver fat content which is NOT linear. Unable to quantify liver fat content on a dynamic range especially when the liver fat ranges 15%-50%. CAP values may impact on the accuracy of liver stiffness especially in patients with higher CAP values and low fibrosis scores (F0-F2). XL-probe may overestimate CAP reading relative to M-Probe.

CT Radiographic features interpreted semi-quantitatively and semi-objectively ( less dense liver = lower HU = darker image) (density of liver to spleen ratio). Exposure to Ionizing radiation. As regard CT of the abdomen, Rarely used to look for NAFLD. Typically incidental finding on abdominal imaging performed for another indication. CT is NOT favored for the assessment of hepatic steatosis due to

MR-PDFF Detect proton signals as a function of their resonance frequency Signal intensity at resonance frequencies of fat and water are measured The fat-signal fraction can then be calculated as the ratio of MR-measured proton density of fat to the sum of fat and water proton densities MRI-based methods can

MR-PDFF Sensitive to detect even trace amounts of liver fat. Accurate to quantify liver fat content. Get an image of the liver (VS. Spectroscopy)→ Know the exact region of interest where fat is measured. Useful for longitudinal assessment of changes in liver fat content. A 30% relative decline in MR-PDFF = two-point reduction in NAFLD activity score = significant decrease in liver fat content = corresponds to = and likely results from

MR-PDFF Unavailable routinely Expensive Impractical to be used in routine clinical care and reserved for clinical trials or epidemiologic studies. May be used in clinical practice when other methods fail or if a critical need to quantify liver fat content (living liver donor LT)

MODALITY CUS CAP CT MR-PDFF COST + ++ +++ ACCURACY POINT OF CARE Standard No ASSESSMENT Qualitative Quantitative Semi-quantitative CAVEATS May fail in cases of obesity and cirrhosis and iron overload Affected by type of probe and fibrosis Ionizing radiation Non suitable for surveillance

ASSESSMENT OF LIVER FIBROSIS Then we will look at how imaging modalities can be used to identify a progressive disease

Liver stiffness is the most common tissue property emerged as a surrogate estimate of hepatic fibrosis stage Liver stiffness measurement (LSM) is quantified by various elastographic modalities The first of which is

VCTE Standard Point-of-care test Real-time estimate of LSM Shear wave propagation examined at fixed liver depth (25-65 mm M-probe and 35-75mm XL-probe) and LSM provided in KPa. It is an US-based elastographic modality considered It provides a

VCTE Quality criteria for clinical application standardized. Limited reliability in morbidly obese individuals (BMI >30 kg/m2).

SWE.ARFI Potential Point-of-care test. Shear wave speed examined and LSM provided in m/sec. Quality criteria for clinical application limited (Await QIBA). Limited reliability in morbidly obese individuals (BMI >30 kg/m2). ARFI may provide more reliable estimate of hepatic fibrosis stage compared to VCTE in individuals with BMI <30 kg/m2. Other US-based elastographic modalities integrated into CUS device and provide an estimate of LSM

US ELASTOGRAPHY Produce similar results when used to assess the presence of advanced hepatic fibrosis. Add value to the routine clinical care as allow for in-clinic diagnosis longitudinal assessment of hepatic fibrosis stage risk stratification of patients with NAFLD All US-based elastographic modalities

MRE Shear wave propagation examined in 2 or 3 dimensions of the entire liver and LSM provided in KPa. Superior to all US-based elastographic modalities for estimation of any hepatic fibrosis stage especially in morbidly obese individuals. A recent more advanced version of elastography technology that also provides an estimate of LSM is MRE

MRE Useful for longitudinal assessment of changes in hepatic fibrosis stage. A 15%-19% relative decline in MRE-derived LSM = 5% reduction in body weight (the lower threshold associated with improvement in liver histology) = significant decrease in liver fibrosis. = corresponds to = and likely results from

MRE Unavailable routinely Expensive Impractical to be used in routine clinical care for screening the millions of individuals with NAFLD at risk of advanced hepatic fibrosis. Multiscan and Multiparametric MRI may have the utility in the assessment of inflammation beyond liver stiffness to diagnose NASH.

MODALITY VCTE SWE.ARFI MRE COST + ++ ACCURACY +++ POINT OF CARE Standard Potential No QUALITY CRITERIA Standardized Limited CAVEATS Increased variability in morbid obesity May fail in case of iron overload

A STRATEGY TO BE CONSIDERED IN CLINICAL PRACTICE

CLINICAL PRACTICE STRATEGY Use a clinical prediction rule such as FIB-4 to exclude advanced hepatic fibrosis and then perform an elastography method to further assess for advanced fibrosis in those who are either in the grey-zone or have a high likelihood of advanced fibrosis. Individuals with BMI <35 kg/m2 may undergo any US elastography modality depending on the availability and the local expertise. MR elastography may be utilized in individuals with BMI >35 kg/m2 if it is available and the cost is not prohibitive.

CONCLUSION All of the imaging modalities currently utilized have a high negative predictive value for exclusion of high-grade hepatic steatosis and advanced hepatic fibrosis MR-based imaging modalities provide the highest diagnostic accuracy for the detection and quantification of liver fat content and for the assessment of fibrosis in NAFLD. Availability and local expertise and the cost of the imaging modality guide the decision for sure.