Implementation of Non-invasive Point of Care Transient Elastography for Evaluation of Liver Disease in Pediatric Populations with Cystic Fibrosis

Summary

The goal of this protocol is to showcase the technique and use of point-of-care transient elastography for pediatric gastroenterologists monitoring hepatobiliary involvement and advanced cystic fibrosis liver disease in persons with cystic fibrosis.

Abstract

Cystic Fibrosis (CF) is an inherited condition that impacts multiple organ systems, one of which is the liver. The presentation and manifestation of liver disease in CF are varied, and there is ongoing research to better understand its etiology and clinical implications. Some studies have shown that liver disease in CF impacts 10% of people with CF (PwCF) by age 10 and 30% by age 30. Screening and monitoring for hepatic involvement in CF continue to evolve as new guidelines and therapies are created.

In 2023, new consensus guidelines were released regarding the evaluation, nomenclature, and monitoring of liver disease in CF. Two new terms define the impact of CF on the liver: CF hepatobiliary involvement (CFHBI) and advanced cystic fibrosis-associated liver disease (aCFLD). Monitoring and evaluation of the progression of liver disease in CF requires close laboratory monitoring in coordination with imaging. A mainstay of evaluating PwCF for CFHBI includes elastography scanning to determine liver stiffness measurements to assess for possible fibrosis. An affordable, portable, and non-invasive approach to complete elastography evaluations is through point-of-care transient elastography (POCTE).

This article will cover the use and utility of POCTE as it pertains to the evaluation of CFHBI and aCFLD in the pediatric CF population. More specifically, this article will provide background information regarding guidelines for when and how to use POCTE in the care of PwCF. It will also provide detailed instructions on how to perform POCTE, how to interpret results, the next steps in care, limitations of POCTE, as well as other considerations in its use. Lastly, this article will describe a quality improvement project implementing POCTE for the first time in a large pediatric CF clinic.

Introduction

The cystic fibrosis transmembrane conductance receptor (CFTR) encodes an epithelial cAMP-activated chloride channel that regulates exocrine mucus secretions within multiple systems, including lungs, pancreas, intestines, intrahepatic bile ducts, gallbladder, sweat glands, and reproductive organs. Errors in protein synthesis of CFTR lead to cystic fibrosis (CF), a disease marked by systemic thickened mucus production, impaired mucus flow, and increased inflammation. CF transmembrane receptor (CFTR) modulator therapies target errors in protein synthesis and correct or stabilize the defective protein causing the disease¹. Effective modulator therapies became widely available and effective at treating cystic fibrosis (CF) in the 2010s, and now 80% of those with CF are eligible for treatment. These therapies are extending and improving the lives of people with CF (PwCF). As patients live longer, a deeper focus on hepatic involvement in CF has arisen. Manifestations of hepatic involvement in cystic fibrosis vary in presentation as well as severity. The two most common manifestations of CF within the hepatic system are elevation of liver enzymes² and hepatic steatosis^3, with many patients progressing to fibrosis. The impact of CF on the hepatic system is well documented and requires close monitoring as the progression of fibrosis can lead to liver failure.

In 2023, the Cystic Fibrosis Foundation, in coordination with many experts in the fields of gastroenterology, hepatology, nutrition, pulmonology, pharmacy, as well as people with CF (PwCF) and their caretakers, created new guidelines for the evaluation of liver disease in CF. These new guidelines establish the criteria for defining liver disease in CF as well as provide recommendations for monitoring¹. Two key terms that were defined are CF hepatobiliary involvement (CFHBI) and advanced cystic fibrosis-associated liver disease (aCFLD)¹. CFHBI is a broad categorization that scores the degree of liver disease early into the progression, while aCFLD defines the point at which the hepatic damage is irreversible (with significant fibrosis or signs of portal hypertension) and may require interventions such as transplant. A more detailed description of these categorizations is beyond the scope of this article, but the readers can refer to the new guidelines for further information¹. Importantly, part of these categorizations is the degree of fibrosis or liver stiffness in the setting of cystic fibrosis as seen on elastography. The current recommendation for measuring liver stiffness includes a baseline liver elastography for those with CFHBI to evaluate the severity of CFHBI or aCFLD¹. Liver stiffness can be measured through several techniques, including MRI with elastography, ultrasound with elastography, and point-of-care transient elastography (POCTE).

POCTE measures the stiffness and steatosis within the liver through pulsatile vibrations via a handheld probe; the vibrations move through the liver and reflect back to the probe⁴. These measures of resistance to movement and the speed at which the vibration waves come back to the probe allow for the interpretation of stiffness and steatosis⁴. This modality allows for outpatient clinic measures of liver stiffness^4,5,6,7,8,9. POCTE, specifically, yields many benefits as it can be completed by physicians, nurses, and technicians in the clinic after a brief training¹⁰. Its results can be read by a trained gastroenterologist and do not require the expertise of a radiologist. This allows for a convenient in-office technique that is time- and cost-saving for patients. Additionally, this imaging can largely be done without the use of sedation, as it is done quickly and painlessly, leading to it being generally well tolerated for patients above the age of 5¹¹. A diagnosis of CFHBI can be established with a liver stiffness above 5.95 kilopascals (kPa) via POCTE, and a diagnosis of aCFLD can be established with measurements exceeding 8.7 kPa^1,11. There is concern that variability in stiffness measurements via POCTE can occur due to intrapersonal and interpersonal variances as well as variances between study populations¹². A likely cause of these differences is the lack of uniformity within the liver with each measure as fibrosis can have a patchy appearance. Still, studies have shown that wide discrepancies in stiffness are likely in the setting of aCFLD. Use of POCTE in the pediatric setting as compared to the adult setting hosts a new set of challenges. First, there is more limited data regarding the use of POCTE in pediatric patients and fewer studies determining pediatric reference ranges. Further, performing these tests can be challenging in younger pediatric patients as it requires the patient to be able to lie still and follow instructions. It is also recommended that patients be fasting for several hours prior to obtaining POCTE as there have been studies suggesting that eating can impact liver stiffness measurements on POCTE⁸. However, in pediatrics fasting can be very challenging depending on the age of the patient (especially infants or young children). There is ongoing research on this topic that has questioned whether differences in fasting compared to non-fasting POCTE leads to clinically relevant differences. One recent study suggested these differences may not be clinically relevant¹³. While there are limitations, the use of POCTE to establish CFHBI and aCFLD is a practical and useful tool to evaluate liver stiffness. In this article we outline the use, clinical application, and interpretation of POCTE results when evaluating for CFHBI or aCFLD.

Protocol

The clinic in which this was implemented was a large pediatric Cystic Fibrosis clinic located in Dallas, TX, with a patient population of nearly 300 PwCF. This project was IRB-exempt given that it was deemed quality improvement. Appropriate positioning of the patient and tool selection is necessary to create accurate liver stiffness measurements. Once properly set up, the probe should be positioned to get the best results, which is followed by the interpretation of the data.

1. Selecting a probe size

1. Use a medium-sized probe first to establish the intercostal space for the patient. If the probe is not in the intercostal space, move to the small or extra-large size probes.
2. In the pediatric population, use a smaller-sized probe in younger and smaller patients. Use a smaller probe if the thoracic perimeter is under 75 cm and the smallest probe available if the thoracic perimeter is under 45 cm.
   NOTE: Smaller probes may not be capable of controlled attenuation parameter (CAP) data collection.

2. Position of patient and operator (Figure 1)

1. Have the patient lie on their back on an exam table with the right side of their body facing the operator (Figure 1A, C).
2. Ask the patient to have their right arm behind their head and their right leg crossed over their left leg. Have them curve or abduct the right side of their body outward to make the right side of the ribcage prominently facing the operator. Remind the patient to lie still for measures to be accurate (Figure 1A, C).
3. Have the operator sit on a chair next to the exam table, facing the patient and the screen of the POCTE with their right forearm resting on the exam table while holding the probe weight. Ask the operator to use their left hand to control the direction and angle of the probe (Figure 1B, C).
4. Have the operator place the probe in the intercostal space perpendicular to the patient, where the xiphoid would intersect the mid-axillary line. If this space is not working well, ask the operator to move up or down one intercostal space (Figure 1B, D).
5. Apply ultrasound gel to the patient where the probe will be placed.

3. Setting up the POCTE

1. Open the patient profile or create a new exam profile by entering the patient's personal information (Figure 2).
2. Be sure to select the correct probe size mode on the machine (Figure 3, brown box).
3. Press the play button to start the exam.

4. Data collection

1. Once the probe is appropriately positioned, press the button on the probe to begin data collection. The patient will feel a vibration coming from the probe.
2. Troubleshooting and appropriate collection (specific to the referenced POCTE machine [see Table of Materials])
3. Ultrasound signal (TM-Mode): When collecting data, monitor the ultrasound TM-mode signal to ensure appropriate data collection. If the signal does not follow a uniform, layered pattern, reposition the probe to correct for fat content, vasculature, structural, lung, or lower lobes of the liver causing disruptions to the signal. Add more ultrasound gel to improve the signal (Figure 4).
   1. Coordinating proper pressure and position: Two large circles appear on the screen, which are blue and orange. These circles should have a check mark to ensure proper position and pressure of the probe in the liver space. Additionally, ensure there are 4 green bars to indicate appropriate pressure applied with the probe to the liver. If unable to achieve it, try moving the probe to a different space, adding more gel, adjusting the angle of the probe, or adjusting the pressure applied to the probe (Figure 5).
   2. Shear wave propagation: Ensure appropriate probe placement by looking at the shear wave map. A parallel wave pattern is needed for data collection. Reposition the probe to remove common errors like A or E waves (Figure 6).
   3. Ten valid measures are necessary to complete the data collection. Make sure that there is not too much variability within the measures collected by ensuring that stiffness (kPa) IQR is under 30% (Figure 3, green and orange boxes).

5. Reading and interpreting the POCTE

1. Controlled attenuation parameter (CAP)
   1. The CAP is a measure of steatosis; report this as the median value of all data points, in decibels per meter (dB/m) (Figure 3, blue box).
   2. Look for hepatic steatosis when values are above 250^14,15.
2. Stiffness (kPa)
   1. Measure stiffness or elasticity (E) in kPa and report as the median value of all data points. (Figure 3, orange box).
   2. Establish a diagnosis of CFHBI if the liver stiffness is above 5.95 kilopascals (kPa) via TE, and a diagnosis of aCFLD with measurements exceeding 8.7 kPa¹.
3. Shear wave
   1. Wave speed aids in determining the stiffness of the liver. Measure wave speed in meters per second (m/s) and report as the median value of all data points collected (Figure 3, orange box).
   2. Establish a diagnosis of CFHBI with a liver stiffness > 1.45 m/s via POCTE, and a diagnosis of aCFLD with measurements exceeding 1.84 m/s¹.
4. Interquartile range (IQR) and IQR/M
   1. IQR represents the interval around the median value where 50 percent of all valid measurements result (Figure 3, orange box).
   2. Divide IQR by the median and express it as a percentage. Use this IQR/M value to evaluate stiffness. Repeat the test if the value is >30%.

6. Next steps based on the results of POCTE

1. Normal measurements
   1. If all measurements are normal, ask PwCF with CFHBI or aCFLD to continue to undergo POCTE annually regardless of normal measurements.
   2. If all measurements are normal and the patient does not have CFHBI or aCFLD, consider delaying POCTE until the patient meets other diagnostic criteria for CFHBI.
      NOTE: Our clinic practice is to obtain POCTE annually for all patients regardless of whether they qualify for CFHBI.
2. Increased stiffness measurements
   1. Once stiffness measurements are elevated to qualify for CFHBI or aCFLD, ask the patients to undergo POCTE at least annually (more frequent POCTE if there are clinical changes sooner).
3. Invalid measurements
   1. If measurements are invalid (IQR/M > 30%), repeat the POCTE as soon as possible.

7. Pediatric-specific considerations

1. Cooperation with Test
   NOTE: Younger patients may have difficulty cooperating with POCTE as it requires them to lie still for several minutes and follow instructions. In our clinic we do not begin considering POCTE until a patient is 3 years old (which is the time at which ultrasound is recommended in CFHBI guidelines) unless there are other concerns.
   1. To try to improve pediatric patient comfort with the test, always use child-friendly language and explain the process of the test. For example, when instructing a young patient to hold their breath, ask them to make bubbles with their cheeks or ask how long they can be a fish and hold their breath. Offer to let the patient see and touch the probe before starting the test. Offer to model the test on their parent/guardian to make them feel more comfortable.
   2. Some patients will not be able to hold their breath as instructed despite coaching. Proceed with the test but note that results may have been impacted.
   3. At times, even after multiple attempts at coaching and trying various methods to help patients complete the POCTE, some patients are unable to. In these cases, terminate the POCTE and attempt again in 6 months to 1 year.
2. Fasting
   NOTE: Fasting can be challenging in pediatrics, especially for young patients. In addition, pwCF are often overburdened by tests and requests. In our practice, we do not require patients to fast for the POCTE.
   1. In patients 10 or older who are undergoing Oral Glucose Tolerance Tests and are going to be fasting for this, obtain POCTE at those visits.

Results

To implement improved liver screening and, specifically, the use of POCTE in our clinic, a quality improvement (QI) project was designed. Quality improvement tools such as Global Aim, SMART Aim, Process Maps, and Key Driver Diagrams were created. Interventions were implemented via Plan-Do-Study-Act (PDSA) cycles, with a total of four cycles. By the last PDSA cycle, with a date range of September 1, 2023, to August 31, 2023, the group scanned 163 unique patients, 174 scans total, with 71.8% of eligible patients having at ...

Discussion

The use of POCTE in clinical settings allows for affordable, efficient, and well-tolerated evaluations of liver stiffness in PwCF^{1,4,5,6,7,8,9}. The new guidelines for evaluating liver disease in CF prominently focus on imaging as patients begin to show signs of hepatic involvement

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
FibroScan or other POCTE	Echosense or other POCTE	N/A	POCTE Machine
Ultrasound Gel	As available	N/A	For use with POCTE
Ultrasound Probe (assorted sizes)	Echosense	N/A	POCTE Probe