The Emergence of Elastography for Cystic Fibrosis Liver Disease

Abstract

Current recommendations [[1]Debray D Kelly D Houwen R Strandvik B Colombo C Best Practice Guidance for the Diagnosis and Management of Cystic Fibrosis-Associated Liver Disease.J Cyst Fibros. 2011; 10: S29-S36Abstract Full Text PDF PubMed Scopus (266) Google Scholar,[2]Flass T Narkewicz MR. Cirrhosis and other liver disease in cystic fibrosis.J Cyst Fibros. 2013; 12: 116-124Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar for screening of cystic fibrosis liver disease (CFLD) in people with cystic fibrosis (CF) include liver biochemistries, complete blood count and abdominal ultrasound to detect evidence of chronic hepatic inflammation and sequelae of cirrhosis, all of which have limited sensitivity and specificity [[1]Debray D Kelly D Houwen R Strandvik B Colombo C Best Practice Guidance for the Diagnosis and Management of Cystic Fibrosis-Associated Liver Disease.J Cyst Fibros. 2011; 10: S29-S36Abstract Full Text PDF PubMed Scopus (266) Google Scholar,[3]Lam S, Nettel-Aguirre A, Biervliet SV, Roeb E, Sadler MD, Friedrich-Rust M, et al. Transient elastography in the evaluation of CFLD: Systematic review and Meta-analysis; J Can Assoc Gastroenterol. 2019 Jul; 2(2): 71-80.Google Scholar. In this issue of JCF, a longitudinal assessment for CFLD at two centers identified a prevalence of 8.8% by the age of 18 years [[4]Gaskin KJ, Fethney J, Cipolli M, Waters D, Zanolla L, Meneghelli I, Dutt S, Assael BM. Occurrence, outcomes and predictors of portal hypertension in Cystic Fibrosis: a longitudinal prospective birth cohort study. J Cyst Fibros. 2020;19:455–459.Google Scholar]. Although elevated liver enzymes were associated with eventual CFLD, they were not predictive for development of disease, suggesting a need for alternative methods of diagnosing CFLD. Novel imaging methods have been proposed to improve upon our detection of clinically meaningful liver disease. Recently, a multi-center study of gray-scale research ultrasound found that heterogeneity of liver parenchyma (vs normal) was associated with a subsequent 9-fold increased incidence of developing a nodular pattern over four years [[5]Siegel MJ Freeman AJ Ye W Molleston JP Paranjpe SM Stoll J Leung D Masand P et al.Heterogeneous Liver on Research Ultrasound Identifies Children with Cystic Fibrosis at High Risk of Advanced Liver Disease: Interim Results of a Prospective Observational Case-Controlled Study.J Pediatr. Feb 2020; : 1-8Google Scholar], which may reflect a cirrhotic or advanced pre-cirrhotic state. While nodularity on imaging may predict advanced liver disease in the hepatology field generally, these findings have not yet been fully elucidated in people with CF. In addition, there is emerging evidence that advanced CFLD with portal hypertension has a non-cirrhotic etiology as well [6Wu H Vu M Dhingra S et al.Obliterative Portal Venopathy Without Cirrhosis Is Prevalent in Pediatric Cystic Fibrosis Liver Disease With Portal Hypertension.Clin Gastroenterol Hepatol. 2019; 17: 2134Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 7Hillaire S Cazals-Hatem D Bruno O et al.Liver transplantation in adult cystic fibrosis: Clinical, imaging, and pathological evidence of obliterative portal venopathy.Liver Transpl. 2017; 23: 1342Crossref PubMed Scopus (19) Google Scholar, 8Witters P Libbrecht L Roskams T et al.Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension.J Cyst Fibros. 2017; 16: e11Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar]. Studies of liver explants and biopsies in children and adults have shown that obliterative portal venopathy and nodular regenerative hyperplasia represent an important pathophysiology of CFLD [[6]Wu H Vu M Dhingra S et al.Obliterative Portal Venopathy Without Cirrhosis Is Prevalent in Pediatric Cystic Fibrosis Liver Disease With Portal Hypertension.Clin Gastroenterol Hepatol. 2019; 17: 2134Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. The assessment of disease progression prior to the development of portal hypertension in CFLD is challenging and has historically relied on invasive liver biopsy, but a single liver core biopsy typically represents only about 1/50,000 of the liver volume and with a patchy heterogeneous disease such as occurs in CFLD, sampling bias is a common problem [[9]Seeff LB Everson GT Morgan TR et al.Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial.Clin Gastroenterol Hepatol. 2010; 8: 877-883Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar,[10]Stotland BR Lichtenstein GR. Liver biopsy complications and routine ultrasound.Am J Gastroenterol. 1996; 91: 1295-1296PubMed Google Scholar. Approaches to assessment of liver fibrosis using various imaging methods have grown and become rapidly innovative recently. Elastography is a technique that measures tissue deformation secondary to external stress applied using a probe. Elastography allows measurement of tissue stiffness reflective of the underlying pathology affecting tissue composition and can be measured by either ultrasound (USE) or magnetic resonance (MRE). In the resulting images, the least deformed regions are the stiffest, while the most deformed regions are the softest. With dynamic shear wave techniques, quantitative stiffness is assessed by tracking shear wave propagation through the liver, with stiffness values calculated by measuring shear wave velocity [[11]Yin M Venkatesh SK Ultrasound or MR Elastography of liver: which one shall I use?.Abdominal Radiology. 2018; 43: 1456-1551Crossref PubMed Scopus (20) Google Scholar]. This technique is increasingly used to detect and stage hepatic fibrosis in the setting of diffuse liver disease. Ultrasound-based approaches include: transient elastography (TE), point shear wave elastography (SWE), and 2D SWE and all have been applied to relatively small cohorts of people with CF often in single center studies. Dynamic USE has two main approaches that are well established in the clinical practice. They are transient elastography (TE) using an extrinsic vibrating source at 40–50 Hz and shear wave elastography (SWE) using an acoustic radiation force at 100–500 Hz [[11]Yin M Venkatesh SK Ultrasound or MR Elastography of liver: which one shall I use?.Abdominal Radiology. 2018; 43: 1456-1551Crossref PubMed Scopus (20) Google Scholar]. TE has the unique advantage as a point of care test that may be performed within clinic that is highly reproducible to measure liver stiffness in a short period of time (often <10 min). As a result, the cost of TE is much lower. The most commonly used device in current practice is Fibroscan™. SWE provides a full dimensional image-based approach compared to TE, which provides only a 2-D image without capability of capturing an anatomical image. Neither are ideal in morbidly obese patients or those with ascites, though impact on reproducibility appears to affect TE more [[14]Fraquelli M Rigamonti C Casazza G et al.Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.Gut. 2007; 56: 968-973Crossref PubMed Scopus (665) Google Scholar]. With SWE, the operator can visualize the interrogated region in detail (e.g. evaluate texture of the liver, exclude masses, evaluate patency of large blood vessels and bile ducts) while conducting elastographic measurements, thus ensuring the proper position. SWE allows assessment of size and contour of the liver, detection of hypertrophy of the caudate lobe associated with advanced fibrosis and ability to detect and monitor focal lesions such as hepatocellular carcinoma or regenerative nodules. While TE may not provide as much anatomic information as SWE, it offers a standardized platform with universal threshold values for liver stiffness, whereas SWE measures may vary by vendor (using different shear wave frequencies) and must be interpreted accordingly [[12]Fang C Konstantatou E Romanos O Yusuf G Quinlan D Sidhu P Reproducibility of 2-dimensional shear wave elastography of the liver.J Ultrasound Med. 2017; 36: 1563-1569Crossref PubMed Scopus (24) Google Scholar]. SWE can be inherently limited due to its operator dependence; however, recent literature shows SWE techniques to have excellent reproducibility [12Fang C Konstantatou E Romanos O Yusuf G Quinlan D Sidhu P Reproducibility of 2-dimensional shear wave elastography of the liver.J Ultrasound Med. 2017; 36: 1563-1569Crossref PubMed Scopus (24) Google Scholar, 13Hudson JM Milot L Parry C Williams R Burns PN Inter- and intra-operator reliability and repeatability of shear wave elastography in the liver: a study in healthy volunteers.Ultrasound Med Biol. 2013; 39: 950-955Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 14Fraquelli M Rigamonti C Casazza G et al.Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease.Gut. 2007; 56: 968-973Crossref PubMed Scopus (665) Google Scholar, 15Ferraioli G Tinelli C Zicchetti M et al.Reproducibility of real-time shear wave elastography in the evaluation of liver elasticity.Eur J Radiol. 2012; 81: 3102-3106Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar]. In a study published in this Issue of JCF, SWE-determined LSM showed good diagnostic accuracy (AUC 0.79) in detecting CFLD in children comparing CF patients with and without CFLD (diagnosed according to guidelines) and healthy controls [[16]Calvopina DA, Noble C, Weis A, Hartel GF, Ramm LE, Balouch F, et al. Supersonic shear-wave elastography and APRI for the detection and staging of liver disease in pediatric cystic fibrosis. J Cyst Fibros. 2020;19:449–454.Google Scholar]. The accuracy improved (AUC 0.84) when combined with aspartate aminotransferase-to-platelet ratio index (APRI). Using a greater threshold LSM, SWE accurately discriminated advanced CFLD (AUC 0.95). These data complement another study of TE used in 160 consecutive children with CF and concluded that this modality showed an AUC of 0.87, using a cut-off value of 8.7 kPa (75% sensitivity and 100% specificity) to detect bridging fibrosis and/or cirrhosis (Metavir fibrosis stage F3-F4) [[17]Lewindon PJ Puertolas-Lopez MV Ramm LE Noble C Pereira TN Wixey JA et al.Accuracy of Transient Elastography Data Combined With APRI in Detection and Staging of Liver Disease in Pediatric Patients With Cystic Fibrosis.Clin Gastroenterol Hepatol. 2019; 17: 2561-2569Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. TE technology also has the capability to quantify liver fat or steatosis using controlled attenuation parameter (CAP). Work by Bader et al. in adolescent and young adult patients with CF did not find that degree of steatosis associated with clinical markers of liver disease, however they interestingly report higher CAP in those with CFLD (n = 44), but not in those with evidence of cirrhosis and portal hypertension (n = 15), suggesting that steatosis may be replaced with fibrosis in more advanced CFLD [[18]Bader RM Jonas MM Mitchell PD Wiggins S Lee CK Controlled attenuation parameter: A measure of hepatic steatosis in patients with cystic fibrosis.J Cyst Fibros. 2019; 18: 280-285Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. While informative, small studies such as these need validation in larger prospective studies. MRE is a phase-contrast based method that utilizes low frequency (60 Hz) mechanical waves to indirectly assess stiffness of the entire liver. A passive driver is secured to the chest/anterior abdominal wall over the liver of the patient during the exam. As the mechanical waves enter the liver, their wavelength changes in response to the underlying tissue stiffness [[19]Leung DH Khan M Minard CG Guffey D Ramm LE Clouston AD et al.Aspartate aminotransferase to platelet ratio and fibrosis-4 as biomarkers in biopsy-validated pediatric cystic fibrosis liver disease.Hepatology. 2015; 62: 1576-1583Crossref PubMed Scopus (57) Google Scholar]. Subsequently, in post-processing, a stiffness heat map (warmer colors reflect increasing stiffness) of the liver, referred to as an elastogram, is generated [[20]Hayes D Krishnamurthy R Hu HH Magnetic resonance elastography demonstrates elevated liver stiffness in cystic fibrosis patients.Journal of Cystic Fibrosis. 2018; 17: 54-56Abstract Full Text Full Text PDF Scopus (6) Google Scholar,[21]Venkatesh SK Yin M Ehman RL Magnetic resonance elastography of liver: Technique, analysis, and clinical applications.J Magn Reson Imaging. 2013; 37: 544-555Crossref PubMed Scopus (408) Google Scholar. MRE and USE each have their advantages (Table 1). MRE acquisition is a two-dimensional algorithm wherein four axial slices are acquired during a breathhold of 20-30 seconds (Fig. 1), although free breathing versions should become available soon. Three-dimensional MRE acquisition is being investigated, which will allow assessment of the entire liver volume, as opposed to just four cross-sectional slices and may help identify the pattern of fibrosis in CFLD that can be quite heterogeneous. It is important to understand that USE and MRE data on liver stiffness measurements (LSM) cannot be extrapolated to one another, since the physics and frequencies captured are distinct for each modality [[22]Tang A, Cloutier G, Szeverenyi, Sirlin C. Ultrasound Elastography and MR Elastography for Assessing Liver Fibrosis: Part 2, Diagnostic Performance, Confounders, and Future Directions; AJR Am J Roentgenol. 2015 Jul; 205(1): 33–40.Google Scholar].Table 1 Transient ElastographyShearwave ElastographyMR ElastographyTechnically easy and relatively fast with good reproducibility, performed in clinicTechnically easy with good reproducibility, performed by sonographerStandardized technique across magnet strengths and vendor specific machines, performed by technician and radiologistCan be performed in younger patients and at the bedside without sedationCan be performed in younger patients and at the bedside without sedationBreath-holding required for MR Elastography sequence, hence may need sedation in younger patientsAbundant literature specific to pediatric CFLD, validated technique in pediatricsEmerging literature for diagnosing and staging hepatic fibrosis in CFLDNormative data and cut-off values specific to CF not yet available, but being studiedLimited performance in obese patients and those with ascitesLimited performance in obese patients and those with ascitesEasily performed in obese patients and those with ascitesLacks full 2-D imaging, thus provides no anatomical information. However, can capture fat fractionDisplayed in real-time, 2-D ultrasound which allows for evaluation of anatomy, vasculature, and steatosisPost-processing on elastograms is performed at each slice level, providing a global assessment of the liverA 50-MHz wave is passed into the liver from a small transducer on the end of an ultrasound probe. Manual compression responsible for some operator dependenceShear waves are generated using acoustic radiation force. Manual compression responsible for some operator dependenceThe low frequency waves are generated by a mechanical drum placed over the abdominal wall overlying the liver Open table in a new tab Early experience with MRE has shown that the technique is both feasible and robust in pediatric patients when utilizing 2-D gradient-recalled echo MRE [[23]Joshi M Dillman J Towbin A Serai S Trout A MR Elastography: high rate of technical success in pediatric and young adult patients.Pediatr Radiol. 2017; 47: 838-843Crossref PubMed Scopus (31) Google Scholar]. There are emerging data on threshold values for hepatic stiffness in pediatric patients without liver disease, with a recent paper reporting higher LSM in healthy children compared to healthy adults [[24]Sawh MC Newton KP Goyal NP Angeles JE Harlow K Bross C et al.Normal range for MR Elastography measures liver stiffness in children without liver disease.J. Magn. Reson. Imaging. 2020; 51: 919-927Crossref PubMed Scopus (14) Google Scholar]. Mean hepatic stiffness value for their study population (81 children, 8-17 years) was significantly greater than reported values for healthy adult subjects. Although the current literature on MRE in pediatric CFLD is sparse, a recent article reported elevated LSM on all four pediatric patients with documented CFLD who underwent MRE. One patient with splenomegaly and portal hypertension had the highest LSM [[20]Hayes D Krishnamurthy R Hu HH Magnetic resonance elastography demonstrates elevated liver stiffness in cystic fibrosis patients.Journal of Cystic Fibrosis. 2018; 17: 54-56Abstract Full Text Full Text PDF Scopus (6) Google Scholar]. While many studies that demonstrate increasing liver stiffness (albeit TE or SWE) with liver fibrosis severity validated by liver biopsies, it should be acknowledged that liver stiffness can be confounded by venous congestion, inflammation, steatosis, and a non-fasting state [[11]Yin M Venkatesh SK Ultrasound or MR Elastography of liver: which one shall I use?.Abdominal Radiology. 2018; 43: 1456-1551Crossref PubMed Scopus (20) Google Scholar,[25]Park SH, Kim SY, Suh CH, lLee SS et al: What we need to know when performing and interpreting US elastography: Clin Mol Hepatol. 2016 Sep; 22(3): 406-414.Google Scholar. Importantly, portal hypertension in CFLD, the most severe form, may be secondary to multilobular cirrhosis [[2]Flass T Narkewicz MR. Cirrhosis and other liver disease in cystic fibrosis.J Cyst Fibros. 2013; 12: 116-124Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar,[8]Witters P Libbrecht L Roskams T et al.Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension.J Cyst Fibros. 2017; 16: e11Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholaror non-cirrhotic etiologies such as obliterative portal venopathy and nodular regenerative hyperplasia (NRH) [[6]Wu H Vu M Dhingra S et al.Obliterative Portal Venopathy Without Cirrhosis Is Prevalent in Pediatric Cystic Fibrosis Liver Disease With Portal Hypertension.Clin Gastroenterol Hepatol. 2019; 17: 2134Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,[26]Dachman AH Ros PR Goodman ZD et al.Nodular regenerative hyperplasia of the liver: clinical and radiologic observations.AJR American journal of Roentgenology. 1987; 148: 717-722Crossref PubMed Scopus (92) Google Scholar. NRH resembles cirrhosis radiologically, so differentiating the two by liver biopsy and/or elastography may influence management in regard to therapeutic options such as liver transplant or portosystemic shunts [[26]Dachman AH Ros PR Goodman ZD et al.Nodular regenerative hyperplasia of the liver: clinical and radiologic observations.AJR American journal of Roentgenology. 1987; 148: 717-722Crossref PubMed Scopus (92) Google Scholar,[27]Krasinskas AM Eghtesad B Kamath PS et al.Liver transplantation for severe intrahepatic noncirrhotic portal hypertension.Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2005; 11: 627-634Crossref PubMed Scopus (122) Google Scholar. TE and MRE are being studied in CF multi-center studies (ELASTIC-CF, NCT03001388 and CFLD MRE, NCT02979340) in hopes of better understanding the utility and interpretation of liver stiffness in CFLD. Elastography offers another tool that can be performed in the radiology department (MRE or SWE) or even at the bedside (TE) that will ultimately complement, but unlikely to replace, a comprehensive history and physical examination to detect or predict portal hypertension in CFLD. However, this promising technology to monitor liver disease progression and treatment response in the age of triple combination CFTR therapy and other emerging therapeutics may in the future be as informative as tissue sampling in people with CFLD. PM Masand: Grant/Research support- CF Foundation, MR Narkewicz: Grant/Research support- CF Foundation, Gilead, AbbVie Consultant- Vertex DH Leung: Grant/Research support- CF Foundation, Gilead, Abbvie, Mirum Advisory board-Gilead, Merck